Multifunctional cell membranes-based nano-carriers for targeted therapies: a review of recent trends and future perspective

Abstract

Nanotechnology has ignited a transformative revolution in disease detection, prevention, management, and treatment. Central to this paradigm shift is the innovative realm of cell membrane-based nanocarriers, a burgeoning class of biomimetic nanoparticles (NPs) that redefine the boundaries of biomedical applications. These remarkable nanocarriers, designed through a top-down approach, harness the intrinsic properties of cell-derived materials as their fundamental building blocks. Through shrouding themselves in natural cell membranes, these nanocarriers extend their circulation longevity and empower themselves to intricately navigate and modulate the multifaceted microenvironments associated with various diseases. This comprehensive review provides a panoramic view of recent breakthroughs in biomimetic nanomaterials, emphasizing their diverse applications in cancer treatment, cardiovascular therapy, viral infections, COVID-19 management, and autoimmune diseases. In this exposition, we deliver a concise yet illuminating overview of the distinctive properties underpinning biomimetic nanomaterials, elucidating their pivotal role in biomedical innovation. We subsequently delve into the exceptional advantages these nanomaterials offer, shedding light on the unique attributes that position them at the forefront of cutting-edge research. Moreover, we briefly explore the intricate synthesis processes employed in creating these biomimetic nanocarriers, shedding light on the methodologies that drive their development.

Keywords:

• Cell-membrane coating
• nanoparticles
• drug delivery
• disease targeting
• nanocarriers

Introduction

The drug delivery field is related to the pharmacokinetic and toxicological assessment of the administered entity, especially the drug in the body after its administration. Traditionally, oral, intravascular, parenteral, inhalational, and topical routes have been used for drug administration. Traditional methods of drug administration have several limitations, as the drug reaches the systemic circulation and is cleared by renal clearance to a greater extent than 90%. Drugs based on proteins, peptides, and genes are also susceptible to acid and enzymatic degradation. As a result, carrier-mediated or innovative drug delivery techniques gained popularity, which maximize the drug’s deposition in the diseased location (Narain et al., 2017). Compared to conventional free drug molecules, nanocarriers-based delivery systems have several clear benefits (Liu et al., 2023). Due to the enhanced permeability and retention (EPR) effect, nanomedicines can extravasate through the leaky tumor site vasculature and concentrate there preferentially (Maeda, 2001; Matsumura and Maeda, 1986; Wang et al., 2012). Some desired characteristics of synthetic nanoparticles (NPs) include prolonged half-life, higher encapsulation, and constant or induced drug release (Davis et al., 2008; Petros and DeSimone, 2010; Barua and Mitragotri, 2013). Depending on their intended use, nanocarriers-based medicines can be designed to exhibit particular physicochemical characteristics, such as size, surface charge, hydrophobicity or hydrophilicity, and shape (Barua and Mitragotri, 2013; Kolhar et al., 2013). These characteristics make it possible to deliver therapeutic medication to targeted sites of action more successfully. Active targeting techniques can enhance the favored buildup of NPs at diseased sites by including targeting ligands, such as peptides, small molecules, antibodies, and aptamers, on the nanoparticle surface (Farokhzad, 2012; Farokhzad et al., 2006; Valencia et al., 2011). Moreover, various biocompatible and biodegradable polymers can be safe and non-hazardous methods of delivering substances in vivo (Acharya and Sahoo, 2011; Gunatillake et al., 2003).

The issue regarding what parameters and principles of design are necessary for choosing the best material arises, given the wide variety of biomaterials that can be used as the building blocks for creating NPs (Yu et al., 2016). Three key goals that NPs must achieve to meet their drug delivery purposes have been identified by studying the effectiveness and limitations of earlier materials. Nanocarriers based medicines need to have an adequate time for circulation that allows them to accumulate at the desired site (Yoo et al., 2010). Additionally, they should selectively target only the affected tissues with minimal effects on healthy tissues (Friedman et al., 2013). They must be made of a biodegradable substance with minimum toxicities and quickly cleared from the body (Naahidi et al., 2013). The basic necessity for nanomedicines to interact successfully with the intricate biological environment of the human body depends on these requirements. The immune system is a significant factor in controlling such delivery systems’ biochemical interactions and ultimate ability.

When a biomaterial is administered to the body, it confronts the immune system, which constantly tries to detoxify and remove it from the body (Zolnik et al., 2010). Due to either their inability to get to their desired site or the immune cells’ neutralizing effect, the therapeutic efficacy of nanomedicines is reduced. On the other hand, immune cell activation is a blessing. It can target various diseases, as in certain conditions, the immune response aids in drawing immune cells toward the site of the illness (Chen et al., 2018). Because of their surface characteristics, nanomedicines can interact with the body’s immune system at the cellular level. The nano-bio interface facilitates these interactions between nanocarrier-based drugs and immune cells, which alludes to a region where the NP surface directly interacts with its biological surroundings (Nel et al., 2009). The interactions at this nano-bio interface decide the immune cell response to the nanocarriers in the bloodstream. As a result, the NP surface’s physicochemical characteristics and composition greatly influence how the immune system perceives them and, consequently, can control their capacity to surmount the immune system’s biological barriers (Liu and Tang, 2017).

Biomimetic nanocarriers, especially cell membrane-based nanomedicine, have seen a growing interest in recent years as they sought to reduce immune system activation. This new drug delivery approach imitates the characteristics and capabilities of native cells while taking advantage of the interactions that naturally occur among both NPs and the biological elements that make up the human organism (Parodi et al., 2017). These formulations mirror donor cells’ physiological features and functions to escape immune clearance and boost therapeutic effectiveness. This is accomplished using entire cells, cell ghosts, and membrane proteins derived from cells (Evangelopoulos et al., 2020). These platforms have shown promising results in overcoming the obstacles presented by the biological and immune systems using biomimicry, focusing on lowering the elimination from the body before they reach their intended target (Perera and Coppens, 2019).

Although studies have explored different cell types, including red blood cells, cancer cells, and stem cells, there is a need for a systematic assessment of their efficacy in specific therapeutic contexts, such as cancer therapy or cardiovascular disease. Furthermore, despite the promising preclinical results, there remains a significant research gap in the clinical translation of these nanocarriers (Liu et al., 2023; Wang et al., 2012; Kolhar et al., 2013). Challenges related to scaling up production, ensuring biocompatibility, and navigating regulatory hurdles require further investigation. In parallel, the market for cell membrane-based nanocarriers presents intriguing dynamics. While there is growing demand, particularly in oncology and targeted drug delivery, a market gap exists in fully meeting this demand due to the complexity and unique challenges posed by these innovative nanocarriers (Yoo et al., 2010; Zolnik et al., 2010).

Moreover, the competitive landscape is evolving, offering opportunities for new entrants to address market gaps, especially in therapeutic areas where existing solutions are limited. Market sizes vary by application and region, with the oncology market representing a significant portion of the overall market. Projections indicate continued growth, driven by advancements in nanotechnology and personalized medicine, underscoring the immense potential and expanding market size for cell membrane-based nanocarriers in the coming years. Therefore, this review aims to provide a thorough literature on the types of cell-membrane-based nanocarriers, characterization, coating techniques, and their application for targeting various diseases.

Cell membrane-based nanocarriers and their functionalization

The cell membrane-based nanocarriers (CMBNC), mainly termed cell membrane-coated NPs (CMCNPs), is a new and intriguing advancement in biomimetic nano-engineering that comprises a core material decorated with a membrane developed from a source cell (Hu et al., 2011). This unique technology can duplicate intricate cellular functions to produce novel therapeutic modalities (Hu et al., 2013). For example, some CMCNPs are excellent long-circulating drug carriers because they can effectively escape clearance by the immune system (Piao et al., 2014). Some affinity ligands in their progenitor cells enable them to target disease sites efficiently. A few CMCNPs provide accurate and more pertinent antigen display by imitating parent cells. Others can detain bacterial toxins, limiting their adverse effects while maintaining their structural integrity (Kroll et al., 2017; Wei et al., 2017). They can function as vaccines that produce incredibly effective protective antibodies owing to these special abilities.

Since their introduction, CMCNPs have increasingly been used in sophisticated biological systems. As a result, the need for multifunctionality and multitasking rises. In some circumstances, adding extra features or functional compounds appears to be advantageous in improving the efficiency of NPs. For instance, although the cell membrane coating impressively provides immune evasion and stealth characteristics, extra target selectivity could further restrict off-target adverse effects and improve therapeutic effectiveness (Tietjen et al., 2018). Although these NPs can effectively transmit antigenic information to facilitate immune uptake, greater and more precise control of the immune stimulation would result in better immunity modulation (Fang and Zhang, 2016).

CMCNPs could have an increasingly active and advanced bio-interfacing capability if more features, such as those sensitive to environmental stimuli, are incorporated (Deirram et al., 2019). Apart from cell membranes, other functionalities incorporation can considerably increase the application of this new class of nanocarriers. Researchers have employed various strategies to add additional characteristics, including conjugation using carboxyl, amine, sulfhydryl, or biotin-based reactions to attach ligands with such nanocarriers (Li et al., 2018). These techniques make it simple to add functional ligands to cell membranes. Cell membrane damage from random chemical reactions, like aggregation of membrane proteins or undesirable phosphatidylserine exposition to the exterior of the membrane bilayers, can frequently impair immune system stability. It was created to conjugate ligands to the linkers sequentially by attaching them to the cell membrane (Hu et al., 2016; Zhou et al., 2016). Although the technique can reduce membrane damage, it may also restrict the available ligands and conjugation density.

Difficulties have inspired a few uncomplicated, non-disruptive techniques ideal for functionalizing the CMCNPs with conventional ligand conjugation. Four different techniques can be used to introduce functional ligands into cell membranes. The first method, the lipid insertion approach, involves creating a compound that combines a ligand, a linker, and a lipid. This compound is then inserted into the membrane bilayer to introduce the ligand. The second approach, known as membrane hybridization, involves fuzing membranes from different types of cells with opposite ligands, thereby enabling functionalization. Another method, the metabolic engineering approach, is also used for functionalization. This approach introduces ligands in natural lipid or oligosaccharide synthesis pathways, resulting in expression on the cell membrane. Finally, the fourth technique is genetic modification, which involves editing the genes to express protein ligands on the cell’s surface (Ai et al., 2020).

Addressing the multifunctionality demands of CMCNPs presents a prominent challenge as their use in complex biological systems continues to grow. To enhance their versatility, strategies such as lipid insertion, membrane hybridization, metabolic engineering, and genetic modification have been explored to introduce functional ligands into cell membranes. Additionally, achieving improved target selectivity is a key challenge, which can be addressed by prioritizing ligands with high specificity for disease sites and the development of ligands with dual targeting capabilities. Precise immune modulation remains an area of interest, with potential solutions including the engineering of CMCNPs to finely control the immune response through controlled antigen release or the incorporation of immune checkpoint inhibitors. Furthermore, enhancing bio-interfacing capabilities by incorporating stimuli-responsive materials is a promising avenue, although it poses challenges in maintaining stability and functionality.

The nano-bio interface

A specific payload and improved targeting to maximize interaction with the desired site are both components of nanoparticle formulations. Effective bio-interfacing is essential for the successful transition of nanomedicines from experimental to real-world use (Blanco et al., 2015). The nanocarriers’ surface reacts directly with the physiological elements of the surroundings in the intricate and ever-changing environment of the nano-bio interface. The size, surface charge, and functionalization of nanocarriers are among the physicochemical characteristics that actively participate in the ultimate interactions. Nanocarriers employ these characteristics to interact with the cells and surrounding tissues. This interaction has also influenced the response of the components of the physiological environment to the nanocarriers. The exchanges that occur while the particles are circulating throughout the body and those that arise in connection to the target tissue comprise the two arms of the nano-bio interface and immune system interactions (Nel et al., 2009). A nanoparticle introduced into the body interacts with a highly intricate immune system that is precise in identifying and eliminating foreign particles. The performance of nanomedicines is rapidly impaired due to the presence and interaction of various cellular and protein-based components in the circulatory system and their interaction with nanomedicines (Moghimi et al., 2012). In addition, the uptake of nano-carriers-based medicine by the reticuloendothelial system (RES) is the primary hurdle that almost all nano-platforms encounter (Nie, 2010). Specific targeting moieties can help enhance the nanomedicines’ efficacy by augmenting site-specific accumulation and reducing nonspecific uptake (Veiseh et al., 2010).

Considering the significance of nanoparticle bio-interfacing, it is now recognized that careful surface engineering is a crucial step in the entire design process. Applying the poly(ethylene glycol) (PEG) polymer coating to the NP’s surface has traditionally been the gold standard for escaping RES clearance (Suk et al., 2016). PEGylation provides steric stabilization in addition to the creation of a hydration layer on the nanoparticle surface. As a result, an undetectable nanoparticle surface that scarcely engages with its surroundings is created, enabling noticeably better blood circulation. Various ligands, such as peptides, antibodies, aptamers, and small molecules, can be attached to the nanocarriers’ surface to increase targeting functionality (Sanna et al., 2014). Synthetic methods for targeting and extending circulation have greatly improved nanocarrier drug delivery, but there is still ample space for further development. PEG reduces nonspecific interactions of the nanocarriers with complex media, but immune reactions to the synthetic polymer have increased, and antibodies against PEG may affect performance after repeated administrations (Yang and Lai, 2015). Furthermore, as more surface functionalities are needed for large-scale manufacturing, the bottom-up approach for ligands’ conjugation becomes more challenging.

Given the challenges faced by synthetic strategies for NPs functionalization, bioinspired nanotechnology—which takes design cues from nature—has garnered interest recently (Fang et al., 2017). This strategy includes using natural materials and imitating bodily traits like shape and flexibility (Fang et al., 2017; Kozlovskaya et al., 2014). Since in vivo interactions between NPs are fundamentally biological, biomimicry is a sound strategy for successful nano-system design as it employs evolution-enhanced natural techniques. Consider the cell that performs particular functions required for its survival alone or as an element of a multi-cellular organism via interactions with various proteins, extracellular components, and other cells. Researchers hope to replicate the remarkable specificity and sensitivity innate in nature by using biomimetic design principles. This trend has led to the developing of a novel class of nanocarriers that incorporate the benefits of both natural and artificial nanocarriers (Kroll et al., 2017). The CMCNPs differ from other NPs because they have a synthetic core covered in a natural cell-membrane layer. Coating of nanocarriers with cell membranes offers a technology platform that yields a straightforward approach for developing nanocarriers with surfaces that exactly duplicate the incredibly complex functionalities necessary for efficient bio-interfacing. NPs coated with cell membranes naturally imitate the characteristics of the cells they originate from, giving them various capabilities, including prolonged circulation and precise targeting of diseases (Hu et al., 2011).

Key challenges include rapid RES clearance of nanoparticles, the need for specific targeting while minimizing nonspecific interactions, limitations of conventional PEGylation methods, and the complexity of ligand conjugation. This study emphasizes the potential of bioinspired nanotechnology, drawing inspiration from nature’s design principles to replicate the specificity and sensitivity of biological systems. Additionally, the use of CMCNPs, with synthetic cores covered by natural cell-membrane layers, offers a promising solution to enhance bio-interfacing, enabling prolonged circulation and precise disease targeting, aligning with the critical analysis of related literature in the field.

Bio-mimetic NPs

Because the first and second generations of active targeting NPs had some drawbacks, scientists turned to nature for ideas when creating NP compositions for particular uses (Qie et al., 2016; Crist et al., 2013). A third generation of NPs (NPs) has been developed to improve the therapeutic traits of NPs in vivo. These NPs can replicate organic functions physically, chemically, or biologically. For instance, calcium phosphate NPs imitate natural teeth and bones’ chemical composition and structural resemblance (Kalidoss et al., 2019).

In the first study on cell membrane coating, published in 2011, researchers used whole cell membranes to cover NPs (Hu et al., 2011). It is possible to accurately maintain the complex nature of the membrane and all of its proteins, lipids, and carbohydrates by instantly mounting the top layer of the cell on the nanoparticle’s outer surface. Hence, many of the traits exhibited by the parent cell can be transferred to the constructed membrane-coated NPs. Red blood cells (RBCs) were first used to illustrate this idea as the source of the membrane (Hu et al., 2011). RBCs, which deliver oxygen throughout the body, are known to last up to four months in individuals. This characteristic makes these cells particularly appealing for nanocarrier drug delivery because they are controlled by RBC surface markers like CD47 and other regulatory proteins (Oldenborg et al., 2000). In the original research, membrane ghosts were initially created by lysing the RBCs in a hypotonic solution, and the membrane was then formed into vesicles by combining mechanical extrusion via porous membranes with sonication. Transmission electron microscope (TEM) images of the resulting NPs showed a core-shell structure with the membrane encasing the core after coextruding them with already formed poly (lactic-coglycolic acid) (PLGA) polymeric cores. Measurements of size and zeta-potential also supported the presence of a membrane coating of the cores. Remarkably, the NPs outperformed a PEGylated control system by maintaining circulation for a prolonged time after being injected intravenously in a mouse model. The natural RBC membrane was credited for this long circulation quality, demonstrating the possibility of functionalizing NPs with cell membrane coatings (Hu et al., 2011).

In summary, the key focus is on the development of a third generation of NPs that can mimic organic functions physically, chemically, or biologically to enhance therapeutic traits in vivo. These bio-mimetic NPs are designed to replicate natural structures and functions for specific applications. An early breakthrough in this field was the use of whole-cell membranes to coat NPs, which allowed for the preservation of the complex membrane structure, including proteins, lipids, and carbohydrates. RBC membranes, known for their longevity and controlled surface markers, were used as a source for the membrane coating. The process involved creating membrane ghosts from RBCs and forming them into vesicles to encase polymeric NP cores. These bio-mimetic NPs demonstrated extended circulation in mouse models compared to PEGylated controls, showcasing the potential of cell membrane coatings in enhancing NP functionality and bio-interfacing capabilities. This approach draws inspiration from nature to create NPs with improved therapeutic potential.

Analyses of the characteristics of membrane-coated NPs

A more profound comprehension of the unique characteristics of Red Blood Cells’ membrane-coated NPs (RBC-NPs) has been made possible by additional research. For instance, it was demonstrated that the RBC’s self-marker CD47 density congruent to parent RBCs was effectively translocated by the membrane functionalization process (Hu et al., 2013). Furthermore, the right-side configuration of the protein, which is required for its correct functionality, was demonstrated using gold immunostaining. This lessens macrophage uptake by enabling CD47 to interact with its matching receptor appropriately. Furthermore, the right-side-out coating was supported again by sialic acid and glycoprotein assays, revealing that the bulk of the carbohydrate fragments from the cell membrane were found on the NPs’ outside (Luk et al., 2014). As trypsinization was used to remove the surface proteins and carbohydrates, RBC-NPs became unstable at biologically relevant salt concentrations, highlighting the significance of these components for nanoparticle stability. According to a separate investigation that used a dye quenching system, the bulk of the membrane on RBC-NPs is oriented upside-down (Fan et al., 2014). The effectiveness of membrane coatings was demonstrated in different research using biotinylated PLGA cores at high enough membrane-to-polymer ratios. The biotinylated PLGA cores cross-linking via streptavidin may be avoided entirely in this process (Luk et al., 2014). It has been shown that an anionic surface charge of nanoparticles effectively promotes membrane coating owing to the charge asymmetry in biological membranes.

In contrast, the positively charged NP substrates engage with the membranes strongly and create a cross-linked network (Luk et al., 2014). Since the first reports on RBC-NPs, employing cell membranes for functionalizing NP surfaces has been widely adaptable, spanning a broad range of nanomaterials coupled with different cells’ derived membranes (Figure 1). Hydrogels or template synthesis methods that allow the in situ formation of the nanoparticulate core can be employed to create CMCNPs in addition to other formats (Wang et al., 2015; Zhang et al., 2015).

Figure 1. Representation of cell membranes coated NPs and their applications. Membrane sources from a range of cell types have been utilized for coating NPs.

The membrane functionalization process effectively translocates the self-marker CD47 density congruent to parent RBCs, which helps reduce macrophage uptake by enabling CD47 to interact appropriately with its receptor. Additionally, the configuration of proteins on the NP membrane, specifically the right-side-out orientation, was demonstrated through gold immunostaining, further enhancing their macrophage-avoiding properties. The presence of sialic acid and glycoproteins on the NP surface confirmed the correct orientation and revealed the importance of these components for nanoparticle stability. The orientation of the majority of the membrane on RBC-NPs was found to be upside-down, as demonstrated by a dye quenching system. Moreover, the effectiveness of membrane coatings was highlighted when using biotinylated PLGA cores with high membrane-to-polymer ratios, allowing cross-linking without streptavidin. The anionic surface charge of nanoparticles was found to promote membrane coating effectively due to charge asymmetry in biological membranes. This section underscores the importance of understanding the detailed characteristics of RBC-NPs, providing insights into their unique properties and the factors influencing membrane coating. It also mentions the adaptability of using cell membranes for functionalizing NP surfaces, extending to various nanomaterials and membrane sources, including different cells’ derived membranes and alternative synthesis methods like hydrogels and template synthesis.

Coating techniques

Cell membrane-coated NPs can be developed in a series of three primary stages as shown in Figure 2. The initial procedure involves isolating the membranes with a hypotonic buffer to lyse the parent cells. Additionally, the centrifugation technique is employed to purify the mixture and achieve the separation of membranes and cellular components (Fang et al., 2018). The centrifugation procedure may vary based on the specific cell type. One essential technique for the isolation of eukaryotic cell membranes involves the use of uneven sucrose differential centrifugation. This method is employed because it effectively separates the cell membrane from other cellular constituents, such as nuclei and various cellular components.

Figure 2. An illustration depicting the membrane isolation and developing membrane-coated NPs systems. Reprinted with permission from ref (Chugh et al., 2021) under a Creative Commons Attribution 4.0 international license.

In contrast, cellular membranes lacking nuclei, such as RBCs, do not necessitate this procedure. Next, the inner core is prepared. The internal cores consist of various synthetic materials such as PLGA, gelatin, liposomes, poly (caprolactone), mesoporous silica NPs, silicon NPs, Fe3O4 NPs, Au NPs, and other similar substances. The selection of the inner core is contingent upon the specific nature of the cargo intended for transportation.

The fusion of membranes and inner core NPs prepares cell membrane-coated NPs. The fusion procedure must be executed to avoid denaturation of membrane proteins or cargo leakage. The two predominant techniques for integrating the internal core with cellular membranes are extrusion and ultrasonic treatment (Zhang et al., 2020; Ma et al., 2020). During the process of membrane extrusion, the membranes undergo sequential extrusion to facilitate their extrusion. In this biological methodology, specimens (comprising a blend of membrane and internal core NPs) are propelled through pores of varying sizes. The precise regulation of the NP-to-membrane ratio is paramount for ensuring comprehensive surface coverage (Xuan et al., 2016). Sonication is being used to facilitate the fusion of the platelet membrane with the PLGA core, which carries a diverse array of proteins recognized by the organism (Mishra and Jain, 2003). The sonication’s temporal, energetic, and rhythmic aspects should be fine-tuned to mitigate the escape of drugs and the denaturation of proteins while simultaneously enhancing fusion efficiency.

The stability of uncoated NP cores and cell membrane-derived vesicles depends on membrane and NP core interactions. It is believed that core-shell conformation with the right-side-out orientation of the membrane is more advantageous concerning the mechanism leading to membrane coating. Other cutting-edge techniques for encasing nanoparticles in cell membranes have been described. Lately, the successful coating of RBC membrane around magnetic NPs has been accomplished using a microfluidic system that employs electroporation and rapid mixing processes (Rao et al., 2017). According to the report, a device with an electrophoretic zone was mentioned just before the outlet. The device also featured an S-shaped mixing channel and a Y-shaped merging channel. High-quality particles with complete coatings and remarkable stability were produced by carefully adjusting the pulse voltage, duration, and flow velocity. Apart from conventional methods that rely on purified membrane components, a new approach has been developed that involves in situ packaging of NPs using living cells (Silva et al., 2013). To create NPs utilizing this method, cells are initially incubated with gold, iron oxide, or quantum dot NPs. These cells are subsequently cultured in serum-free media to secrete vesicles with exogenous NPs.

The above data highlights the critical steps in developing CMCNPs. The process involves three primary stages: 1) isolating cell membranes from parent cells using a hypotonic buffer and centrifugation, 2) preparing the inner core with various synthetic materials based on cargo requirements, and 3) fuzing the membranes with inner core NPs using extrusion or ultrasonic treatment methods. The precise control of NP-to-membrane ratios is crucial for comprehensive surface coverage, and the right-side-out orientation of the membrane is preferred for optimal coating stability. Additionally, cutting-edge techniques, such as microfluidic systems for coating magnetic NPs and in situ packaging using living cells, are described, demonstrating the versatility and advancements in CMCNP synthesis. These techniques offer researchers various approaches to tailor CMCNPs for specific applications, leveraging the unique properties of natural cell membranes for therapeutic delivery and bio-interfacing.

Applications of cell membrane-based nanoparticles

Scientists can reap the best of both worlds by fuzing synthetic and natural materials. It is possible to precisely adjust the synthetic core of membrane-coated NPs to exhibit distinct characteristics and load-specific therapeutic agents. Using the natural cellular membrane component, functionalities that would be difficult or unfeasible to achieve through traditional chemical approaches can be attained (Peer et al., 2020). The potential of using cell membrane-coated NPs in delivering therapeutic agents for various diseases is significant as they take advantage of the inherent functions of the source cell membranes. Despite being a relatively recent discovery in nanomedicine, these biomimetic NPs have shown tremendous potential in delivering nanoparticle-based drugs (Gao et al., 2013; Gao and Zhang, 2015).

This article focuses on the therapeutic principles and applications of cell membrane-coated NPs, and it also includes a discussion on their potential future developments and some of the challenges faced in this field.

Cell membrane-based nanoparticles for cancer therapy

To achieve tailored delivery to the tumor site, researchers have investigated several cell-membrane coatings across the years, such as RBCs, leukocytes, neutrophils, apoptotic bodies, and cancer cells (Pasto et al., 2019; Yi et al., 2023; Zhang et al., 2022). Cancer-targeted cell membrane-based NPs have successfully imitated several different kinds of natural cells. RBC-based NPs utilize the benefits of producing ‘don’t eat me’ markers, such as CD47, to increase the period in blood circulation and escape from the damaging effects of MPS to reach the desired tumor target (Sun et al., 2019). Similar techniques have been employed to impart these characteristics to NPs using leukocyte membranes. These biomimetic NPs are marked for elimination by the MPS because they mimic native immune cells in form and do not interact with circulating monocytes (Corbo et al., 2017). As a result, when their circulation behavior is replicated, these NPs have a better chance of reaching the targeted tumor site. Neutrophil membrane-coated NPs successfully transport themselves to tumor sites through neutrophil hitchhiking, utilizing their inherent affinity for tumors (Yu et al., 2023). This immunosuppressive microenvironment regulation enhances tumor immunotherapy’s efficacy as the NPs effectively navigate the immune cells (Yu et al., 2022). Apoptotic bodies play a crucial role in facilitating intercellular delivery, thereby improving the penetration of drugs. Applying apoptotic body-coated NPs has demonstrated remarkable therapeutic efficacy in addressing tumor metastasis, distant tumors, and primary tumors and preventing recurrence (Sheng et al., 2023).

RBC coated NPs

RBC-covered NPs, containing self-markers such as CD47 and CD59, complement factor 1, decay-accelerating factor, C8 binding protein, and other markers that get past the immune system, were the first CMCNP to be chosen as a delivery mechanism (Narain et al., 2017). In 2014, Barclay and colleagues made it abundantly apparent that the RBC membrane’s CD47 receptor interacts with alpha (SIRP alpha), a protein regulating signals found on macrophages/phagocytes, to produce a ‘do not eat me’ signal that allows NPs to bypass the RES (Xia et al., 2019). Stem cells and RBCs commonly fail to efficiently target cancerous cells as they lack particular homophilic cell adhesion molecules that could otherwise enhance targeting. To give such cell membranes an added advantage and to successfully internalize to targeted cells, ligand moieties, such as folate, mannose, etc., are incorporated in such systems. Specific proteins must be functionalized on RBC-coated NPs to be internalized effectively by the tumor cells. For conjugating ligands or targeting moieties, a non-disruptive lipid insertion approach is usually employed as chemical methods risk damaging proteins in membranes and yielding unsatisfactory results. A lipid insertion strategy was proposed by Fang et al. that involves the functionalization of RBC membranes with lipid-tethered ligand molecules. They used folate and the nucleolin-targeting aptamer AS1411 as ligands, having varied molecular weights (Fang et al., 2013). Lipid tethers were used in this technique to insert ligand moieties onto RBC membranes. It was linked using PEG from MW 2000. The aptamer AS1411 having GGT GGT GGT GGT TGT GGT GGT GGT GG sequence was modified, and they used commercial folate-PEG-lipid. A 1 mg/ml aptamer solution was added to thiol for reducing the disulfide bonds before being combined with maleimide-PEG lipid to produce AS1411-PEG-lipid. Folate-PEG-lipid was combined and extruded with RBC ghosts at a preset concentration to produce tiny, adaptable vesicles for ligand functionalized RBC ghosts. These functionalized RBC based vesicles were then extruded with cores made from PLGA to obtain RBC-Ligand functionalized NPs. Targeted RBCNPs had greater fluorescence intensities than non-targeted RBCNPs, demonstrating that AS1411-aptamer or folate-conjugated RBC coated NPs were successfully internalized by adenocarcinoma human alveolar basal epithelial to (A549) cells. Both groups’ cytotoxicity profiles were relatively comparable, and even at 1000 g/ml, they were safe.

Mannose-modified RBC-coated PLGA NPs were created by Guo et al. to target APCs in the lymph (Guo et al., 2015). Additionally, ligands can be functionalized on RBCNPs in this manner. Chemical moieties or lipid binding can facilitate the conjugation of various ligands. Then, NPs with improved internalization capacities are coated with these improved RBC membranes. In 2011, Hu et al. coated PLGA NPs with RBC membrane vesicles to increase their time in circulation (Hu et al., 2011). To maximize doxorubicin and methylene blue, a photodynamic agent, internalization into MCF-7 and Hela cells, Bidkar et al. constructed PLGA NP enclosed within the RBC membrane. An improved anti-proliferative impact was produced by combining chemotherapy with photodynamic treatment. Transferrin (Tf)-conjugated RBCNPs containing the drug and MB demonstrated a higher degree of apoptosis even though the IC50 did not change substantially in both instances of RBCNPs and Tf-conjugated RBCNPs. After successfully attempting the tests in 2D monolayer cells, further experiments were carried out in 3D spheroids. Additionally, Tf-conjugated RBC-coated NPs showed excellent penetration capability in the 3D spheroid model, as CLSM and fluorescence intensity showed. Chemotherapy combined with photodynamic therapy was successful when 3D spheroids were treated, as evidenced by the marked decrease of IC50 that revealed a synergistic impact of the two components encased within the RBC-Tf coated PLGA NPs (Bidkar et al., 2020).

Zhu et al. created a novel approach for targeted chemotherapy and photothermal therapy against 4T1 cancer cells using RBC-coated gold nanocages loaded with paclitaxel and modified with Epcam antibodies. By exposing the cancer cells to NIR radiation, the RBC-Epcam antibody-targeted Au NPs successfully delivered the drug, resulting in a significantly reduced cell viability with a survival rate of only 25%. This demonstrates the effectiveness of targeting tumors with elevated expression of Epcam antigen and utilizing an NIR laser with an intensity of 2.5 W/cm² (Zhu et al., 2018). Employing 4T1 cells as a model breast cancer cell line, Li et al. created a new technique for imaging triple-negative breast cancer using multiple modalities. They utilized the hypotonic treatment and extrusion method to create DSPEPEG-FA-conjugated RBC-coated up-conversion NPs (UC NPs). These RBC@FA-conjugated UC NPs effectively facilitated MRI and PET imaging in an in vivo model (Li et al., 2020). Liang et al. developed a strategy using RBC-coated black phosphorus quantum dots to trigger apoptosis in breast cancer cells using near-infrared laser irradiation (Liang et al., 2019). The formulation showed extended circulation and specific accumulation in tumor tissues. After being exposed to radiation, the basal-like 4T1 breast cancer exhibited necrosis and apoptosis and dragged in dendritic cells to collect antigens associated with the tumor in vivo. The combination of RBC and quantum dots facilitated aPD-1 and PTT treatment, resulting in substantial retardation in the progression of tumor growth.

It is now widely recognized that RBCs have a prolonged lifespan and inherent ability to evade the body’s RES (reticuloendothelial system), making them well-suited for various biomedical applications beyond traditional drug delivery. Applications like targeting, imaging, and different types of photodynamic therapy fall under this category.

WBC coated NPs

Five main types of white blood cells (WBC), including monocytes/macrophages, neutrophils, eosinophils, basophils, and lymphocytes, are differentiated through their granularity and morphology. However, only some of these cells have been explored in drug-delivery systems. Macrophages are among such cell types that can be harnessed for drug delivery, as they can be home to sites of inflammation and tumors in response to chemotactic agents like colony-stimulating factor (CSF-1) and chemokine ligand-2 (CLCL-2) in hypoxic areas (Dong et al., 2017). Sun et al. developed a unique drug delivery system that employs a macrophage-coated nanoparticle (NP) with a PLGA core. This system uses peripheral and transmembrane intrinsic macrophage membrane proteins coupled to the T7 peptide, binding only to transferrin receptors on tumor cells. They used RAW 264.7 macrophages because of their capacity to localize to inflammatory and tumor locations. The macrophage-coated NP was then used to encapsulate Saikosaponin-D (SsD), a triterpene saponin with steroid-like properties that is abundant in Bupleurum falcatum and functions as an anticancer agent by inducing apoptosis (Sun et al., 2020). In vitro cell uptake and cytotoxicity profiles of LO-2 (normal human liver cell line), 4-T1, RAW-267, and MCF-7 cell lines revealed that the drug-loaded macrophage-membrane coated NPs (SMNPs) displayed higher absorption in tumor cells (4-T1 and MCF-7) and a decreased fluorescence was noted for LO-2 and RAW-267.

Similarly, SMNPs were less harmful to normal cells than only SsD and bare PLGA NPs while having a higher cytotoxic impact on cancer cells. In vivo studies discovered that the group treated with SMNPs had fewer pulmonary metastatic tumors. PBS and SMNPs were used to evaluate in vitro toxicity as well. After one month, there were no pathological changes in the heart, liver, spleen, lung, or kidney. The phosphorylated forms of the Akt and Erk proteins were found in lower concentrations in the SMNP-treated mice, demonstrating that the Akt signaling pathway was the likely target of the SMNPs (Chen et al., 2016).

A neutrophil is the initial form of white blood cell to be mobilized or directed to an injury site, an inflammatory reaction, or a tumor. This process of transmigration is made possible by various adhesion molecules, including beta-1 integrin and LFA-1. These molecules mainly exist on endothelial cells and neutrophils as receptors (De Oliveira et al., 2016). To address the issue of arthritis, Zhang et al. created PLGA-coated NPs, which were covered with the external protein composition of neutrophils. These NPs coated with neutrophils could safeguard cartilage, penetrate cartilage, and obstruct inflammation in synovial fluid, improving arthritis conditions. Using an in vitro model and a human arthritis model in mice, Zhang et al. demonstrated that the neutrophil-cloaked NPs effectively improved the arthritis condition (He et al., 2018).

NK cells, a granulocyte type, release perforins and granzymes for targeting cancerous cells (Suck et al., 2016). To treat breast cancer, Pitchaimani et al. designed ‘NKsome,’ which involved fuzing DOTAP, DOPE, and cholesterol-containing liposomes with NK-92 cells and encapsulating doxorubicin to target cancer cells in vitro and in vivo. The NKsome exhibited its effect for 18 hours after administration (Pitchaimani et al., 2018). Furthermore, Han et al. developed PLGA-lipid NPs coated with N3-labeled T-cell membrane and labeled with indocyanine green to mimic T cells and target Burkitt’s lymphoma. They used a new approach by introducing bicyclenonyne (BCN)-modified unnatural sugars (Ac4ManN-BCN) to cancer cells to enable dual targeting. After administering the nano-formulation intravenously, laser irradiation was applied for 5 minutes. Among the three groups tested, N3TINPs exhibited a significant tumor ablation capacity, reaching 53 °C, while ICGNPs reached 41 °C and PBS was ineffective in tumor ablation, reaching only 36 °C (Han et al., 2019). T cell-coated PLGA NPs were used in different research by Zhang et al. to target gastric cancer. A low-dose local irradiation was used as a chemo-attractant to improve targeting. The findings revealed a 23.99% decrease in the uptake of NPs by macrophages, and tumor volume in Balb/c nude mice decreased by 56.68% by NPs coated with T cells loaded with paclitaxel (Zhang et al., 2017).

The above case studies suggest that using WBC-coated NPs can be a practical approach for targeting tumors and achieving success in drug delivery and photothermal therapy. Therefore, it is reasonable to conclude that coating NPs with WBCs can provide various therapeutic benefits due to the inherent immune evasion properties of WBCs, particularly macrophages. This presents a significant advantage in translational science.

Platelet membrane-coated NPs

With a 10-day lifespan and various immunological functions and metastasis models, platelets develop from megakaryocyte progenitor cells (Thon and Italiano, 2012). Like RBCs, platelets lack a cell nucleus and can be extracted using the same membrane extraction protocol (Liu et al., 2019). The platelet membrane contains several proteins, including CD47 (which aids in macrophage evasion), p-selectin, and CD44. P-selectin attaches to adhesion molecules like CD44 and CD55/59, enabling it to have a strong affinity for circulating tumor cells and preventing complement-mediated immune activation (Li et al., 2018). Additionally, platelets were observed to trigger platelet aggregation, which relies on glycoprotein (Gp)-IIb/IIIa receptors and can be crucial in controlling angiogenesis. The advantage of coating the inner core of NPs with platelet membranes with these different adhesive glycoprotein membrane proteins is that they help them escape macrophages and improve their targeting ability. The PLGA NP core was created by Wang et al. using Vit-E-TPGS as an emulsifier and conjugating them with chitosan (CS) to render the system hydrophilic. This core contained the anticancer drug bufalin and was covered in a platelet membrane (PLTM). The research supported that p-selectin on platelet membranes coated with NP can bind to CD44+ tumor cells to adhere to them (Wang et al., 2019). The results of the ex-vivo cytotoxicity tests showed that both the PLTM-PLGA-CS NPs and bare CS-PLGA NPs were non-cytotoxic up to 500 μg/ml. Nevertheless, a 7.4 times greater cellular uptake was observed for the PLTM-PLGA-CS NPs compared to PLGA-CS NPs, and the viability of the cells dropped to 17.9% when 20 μg/ml of Bufalin in PLTM-CS-PLGA NPs was used. The fluorescence signals of PTM-PLGA-CS NPs were significantly stronger than those of PLGA-CS NPs even after 6 hours and 24 hours post-injection in the mice model, indicating that the biomimetic NPs had good targeting ability.

It is common knowledge that the binding of platelets to molecules on atherosclerotic plaques causes the migration of monocytes and T-cells to the inflammatory site, sensitizing the plaques (Gawaz et al., 2008). Rapamycin, a potent immunosuppressant against atherosclerosis, was enclosed in a platelet membrane-coated PLGA NP (PNP) that Song and coworkers created in 2018. A glycoprotein (Vwf), collagen, and fibrin were used to attach the PNPs to sclerosis. Apolipoprotein E-deficient mice (Apo E -/- mice) have been employed for in vitro studies because the Apo E protein transports LDL particles and controls the release of cholesterol from macrophages, which controls immune responses (Greenow et al., 2005). The PNPs were 8.34 and 9.61 times more efficient at binding to collagen and fibrin clots than the NPs were at doing so. The researchers looked at the aggregation profile of PNPs and Rap-PNPs in macrophages, which are involved in forming atherosclerotic lesions through internalizing LDL and developing into foam cells. The aggregation of PLTM@PLGA NPs was substantially greater than that of bare NPs in the atherosclerotic plaques of Apo E-/- mice, with a 4.98 times increase in radiance energy. Sudan red-stained Apo E-/- mice showed a decrease in lesions of the plaque area following therapy with Rap-PNPs. The heart, brain, liver, spleen, and lungs did not suffer any damage from the treatment, according to H&E staining. Blood biochemistry analysis also revealed that the treatment had no adverse effects on hepatic and kidney functions (Song et al., 2019). In a similar study, He et al. developed platelet-camouflaged PLGA NPs loaded with an immunosuppressive drug called FK506 for treating Rheumatoid Arthritis (RA). The outcomes showed that platelet NPs had increased accumulation in the joints of a mouse model of collagen-induced arthritis (CIA) and better-targeting ability toward inflamed endothelium. The enhanced targeting ability was achieved by using the P-selectin and GPVI receptors (He et al., 2018). In their research, Wu et al. established polypyrrole NPs, which exhibit strong conductivity, act as photothermal agents, and are modified with a platelet membrane to encapsulate doxorubicin. The resulting NPs were used with 808 nm laser irradiation to treat hepatocellular carcinoma (HCC) in an orthotopic mice model (Zhu et al., 2016). This novel NPs system served as a more effective model for anticancer therapy because it not only helped target HCC but also eliminated tumor cells following irradiation with laser. Elevated temperature caused the platelet membrane rupturing and led to drug release at the tumor site.

Platelets may be used as a superior form of stealth or biomimicking material and offer adequate coating around NPs for better therapeutic outcomes because of all the self-leveraging proteins that target areas of inflammation and injuries. Platelets have good biocompatibility and low immunogenicity profiles.

Cancer cell membrane-coated NPs

NPs (NPs) for oncological uses can be wrapped around cancer cell membranes very effectively (Fang et al., 2018). Cancer cells can be readily cultured in large quantities in vitro due to their toughness for mass membrane collection. Additionally, unlike most membrane donors, they can self-target identical cells (Shi et al., 2017). Due to this unique property, cancer cell membrane-wrapped NPs (CCNPs) can target primary tumors and metastatic nodules homotypically (Sun et al., 2016; Fang et al., 2014). Additionally, in tumor cells that are identical to the cells through which they were generated, CCNPs exhibit extraordinary binding and selective uptake. Compared to non-coated NPs, they also show less immune clearance after systemic delivery (Sun et al., 2017; Zhu et al., 2016). These exceptional qualities make CCNPs ideal for nano vehicles to enhance tumor imaging, allow localized phototherapy, improve chemotherapeutic drug delivery, or stimulate immune modulation.

Doxorubicin (DOX) is a medication frequently used to treat breast cancers, ovaries, and other types, such as lymphomas and leukemias (Lovitt et al., 2018). Numerous studies demonstrated that membrane-wrapped NPs (NPs) containing DOX benefit from freely administered DOX (Liu et al., 2019; Tian et al., 2017). For instance, PLGA-DOX NPs coated with membranes from HepG2 hepatocarcinoma cells were created by Xu et al. and successfully transported the drug to Hep2G tumors in mice. Moreover, compared to freely delivered DOX, the cancer cell membrane-wrapped NPs showed less systemic toxicity. This decreased toxicity was ascribed to increased DOX accumulation at the tumor site and reduced off-target proliferation due to the particles’ lack of premature release (Xu et al., 2019). Paclitaxel (PTX) is another chemotherapeutic agent clinically used to treat various cancers, such as AIDS-related Kaposi sarcoma, breast cancer, non-small cell lung cancer, and ovarian cancer. Researchers have explored the potential of combining PTX with membrane-wrapped NPs (NPs) (Armstrong et al., 2006; Sparano et al., 2008). Pluronic copolymer and PCL cores were loaded with PTX and then covered in membranes made from 4T1 murine mammary breast cancer cells. The PTX-loaded polymeric NPs targeting homologous cancer cells and transport medications were investigated in the 4T1 in vivo tumor model. In orthotopic mammary tumor models and mouse models of blood vessel metastasis, these NPs effectively targeted and inhibited the growth of metastatic nodules and homotypic 4T1 primary tumors, resulting in 6.5-fold lower metastatic nodules compared to unwrapped NPs. The 4T1 cell membrane wrapping, which was still intact, enhanced the circulation time of the NPs and reduced phagocytic uptake, which improved the anti-tumor effect of the drug payload (Sun et al., 2016).

CCNPs can also encapsulate multiple cargoes with synergistic effects, delivering them to the same tumor cells to enhance anticancer effects. To combat hypoxia-induced chemoresistance, hemoglobin (Hb) and DOX were encapsulated in PLGA cores and covered with MCF-7 human breast cancer cell membranes and a PEGylated phospholipid. The nanocarriers suppressed hypoxia-inducible factor-1, multidrug resistance gene 1, and P-glycoprotein expression, allowing for safe and effective O2-interfered treatment by lowering DOX exocytosis. Due to the retention of cancer cell adhesion molecules on the NP surface, the CCNPs also displayed higher tumor specificity and reduced DOX toxicity (Tian et al., 2017). This showed the capability of CCNPs to administer multiple therapies. The development of CCNPs for the transport of DOX in combination with siRNAs targeted against PD-L1, a gene commonly overexpressed on tumor cells and whose inhibition may enhance the anti-tumor immune response, was accomplished by Chen et al. using similar approaches. The PLGA NPs were filled with cargoes, and homotypic targeting was made possible by coating the NPs with membranes from HeLa cervical cancer cells (Chen et al., 2019). The HeLa cells preferred the CCNPs over the untargeted MDA-MB-231 breast cancer cells, and the CCNPs successfully repressed PD-L1 expression and decreased cell viability. However, additional research is required to assess the system’s effects on living organisms in vivo. Ye et al. developed a customized photothermal vaccine using surgically excised tumor cells and black phosphorus quantum dots (Ye et al., 2019). The vaccine was incorporated with a PD-1-blocking antibody to prevent tumor recurrence and spread to distant sites. It was embedded into a thermally responsive hydrogel that already had LPS and GM-CSF in it. The nano-system’s hypodermic injection facilitated the continuous release of GM-CSF, efficiently attracting dendritic cells to capture tumor antigens. NIR irradiation and stimulation of LPS resulted in the proliferation and activation of dendritic cells. Subsequently, these dendritic cells migrated toward the lymph nodes, where they engaged in presenting antigens to CD8⁺ T cells.

Notably, using cancer cell membrane coatings in various NP platforms has no adverse effects on drug loading. The studies discussed above indicate that CCNPs hold great potential in improving drug delivery to specific sites, thereby enhancing the safety and efficacy of the treatment. These outcomes offer exciting opportunities for the development of novel therapeutic approaches.

Stem cell-coated NPs

Mesenchymal stem cells (MSCs) possess a distinctive characteristic of long-term proliferation, allowing them to remain in the bloodstream for extended periods. These cells can also evade the immune system and have receptors targeting tumor cells specifically (Liu et al., 2019; Uccelli et al., 2008). Moreover, MSCs are readily isolated and can be generated from various tissue types, offering a vast range of possibilities for therapeutic purposes (Uccelli et al., 2008). To develop gelatin nanogels coated with stem cell membranes that contained Dox, Gao et al. first made stem cell membrane vesicles. Then, they combined them with gelatin nanogels employing a polycarbonate membrane. Unadorned NPs demonstrated no toxicity up to 400 μg/ml after 24 hours. HeLa cells exhibited nearly 100% uptake of SCMGs-DOX, and cy7-SCMGs showed significant accumulation in the tumor region, as evidenced by fluorescence intensity. The amount of SCMGs in the spleen, kidney, liver, and lung was also minimal (Gao et al., 2016). To induce apoptosis in DU145 cells, a human prostate cancer cell line, Mu et al. developed polydopamine-coated iron oxide NPs modified further via MSCM enclosing siRNA against the Plk1 gene. Both cell cultures and mouse models were employed for assessing the different nanoparticle groups. The findings showed that the MSC coating, which received some heat because of the lipid bilayer of the stem cell membrane, was nearly equal to that of MSC-Fe₃O₄-PDA NPs-Plk1 in terms of photothermal conversion energy. However, there was enough energy left for ablation to occur (Mu et al., 2018). During MRI scanning, T2 is a measure of how long it takes the signal to fade. MSC-Fe3O4-PDA NPs-Plk1 did not significantly affect normal 293t cells in the in-vitro system at 200 μg/ml or higher. 90% of the DU145 cells died after being exposed to laser radiation for five minutes consecutive after being treated with polydopamine-coated iron oxide NPs. The viability of cells was not dramatically reduced by NIR laser without the help of NPs, though. Fe3O4@PDAsiRNA@MSCs NPs’ tumor inhibition efficiency reached 60% following 15 days of laser therapy, and HE staining verified that there was no discernible necrosis or inflammation in the major organs (Mu et al., 2018). Bose et al. conducted a study where they developed a CXCR4 antibody-coated PLGA NPs functionalized stem cell membrane for targeting ischemic tissue. The NPs penetrated the endothelial barrier thanks to the MSC coating, which decreased cell uptake by human (THP-1) and mice (J774) macrophages. After a 14-day treatment, the NPs were retained in the ischemic tissue (endothelium) (Bose et al., 2018). Gao and colleagues developed a system by cloaking mesoporous silica NPs with MSCs and then encapsulating photosensitizers (β-NaYF4:Yb3+, Er 3+) loaded with ZnPC and MC50. Upon laser irradiation at 980 nm, these NPs showed effective anti-tumor activity. These examples show how MSC-coated NPs may circulate in the body for long periods without being detected by the immune system by substituting ligands for tumor cell-coated NPs that allow them to pass the endothelial barrier (Gao et al., 2016).

Cell membrane-coated NPs offer a promising avenue for advanced biomedical applications. These NPs are designed by encapsulating synthetic cores within natural cell membranes, providing them with unique properties. RBC-coated NPs with markers like CD47 extend circulation and enhance tumor targeting, while WBC-coated NPs, such as macrophage or neutrophil-coated ones, find applications in drug delivery to inflammatory sites or tumors. Platelet membrane-coated NPs, with adhesive glycoproteins, evade the immune system and target diseases like atherosclerosis. Cancer cell membrane-coated NPs display homotypic tumor targeting, enhancing drug delivery safety and efficacy, and stem cell-coated NPs, specifically MSC-coated ones, offer long circulation times and immune evasion. These biomimetic NPs hold great promise for targeted drug delivery, immunotherapy, and tissue-specific treatments, fostering innovative approaches in biomedical research. The examples and characteristics of various typical cell membrane-coated NPs and their application is given in Table 1.

Table 1. The advantages and characteristics of typical cell membrane-coated NPs and some examples of their application in different therapies.

Membrane Types	NPs Cores	Therapy Type	Advantages	Potential Drawbacks	Refs.
RBC	PLGA, Fe3O4, Au, and black phosphorus quantum dots	Immunotherapy, chemotherapy, PTT, PDT, and gene therapy	Biocompatibility, long circulation, hypo-toxicity, and immune escape	Poor targeting and inducing unnecessary immunological reactions	(Bidkar et al., 2020; Zhu et al., 2018; Liang et al., 2019; Yu et al., 2023)
WBC	PLGA, and Fe3O4	Immunotherapy, chemotherapy, and PTT,	Biocompatibility, homologous targeting, long circulation, transendothelial migration, and reducing opsonization	High heterogeneity	(Pitchaimani et al., 2018; Han et al., 2019; Ruan et al., 2022)
Platelet	PLGA, Fe3O4, and Au nanorods	Immunotherapy, chemotherapy, PTT, PDT, and gene therapy	CTC-targeting, Subendothelium binding, Low immunogenicity, and Immune escape	Cause aggregation and low blood concentration	(He et al., 2018; Wang et al., 2019; Song et al., 2019; Zhu et al., 2016)
Cancer cell	PLGA, Au nanocages, mesoporous silica NPs, and	Immunotherapy, chemotherapy, PTT, PDT, and gene therapy	Homologous targeting, anti-tumor response, and immune escape	High cost and unknown pathogenicity	(Sun et al., 2016; Sun et al., 2017; Liu et al., 2019; Ye et al., 2019)
Stem cell	PLGA, Gelatin, Fe3O4, and black phosphorus quantum dots	Immunotherapy, chemotherapy, PTT, PDT, and gene therapy	Tumor-homing affinity and homologous targeting,	High cost	(Gao et al., 2016; Mu et al., 2018; Bose et al., 2018)

Cell membrane-based nanoparticles for cancer therapy

Instead of utilizing aspects of the tumor microenvironment like specific enzymes or low pH to allow targeted drug release, one strategy to achieve tumor-specific treatment is to employ NPs that are inactive until they become activated by external light. The two primary applications of this strategy are photothermal therapy (PTT) and photodynamic therapy (PDT), both currently being investigated in conjunction with membrane-wrapped NPs. PTT involves injecting NPs with unique optical characteristics into tumors, which are then subjected to near-infrared light, which produces heat that can harm cancer cells (Valcourt et al., 2019; Riley and Day, 2017). Similar to this, in PDT, photosensitizers are injected into tumors, and as a result, the tumor is exposed to radiation, which transfers the energy absorbed from the tumor to oxygen molecules in the surrounding tissue, creating toxic singlet oxygen that destroys cancer cells (Riley et al., 2018; Melamed et al., 2015). Most studies have coupled cancer cell membranes with other therapeutic modalities, even though some membrane-wrapped NPs have only been used in PTT or PDT using non-cancer cell membranes (Melamed et al., 2015). Using membrane-wrapped NPs in these strategies has shown promising results for achieving targeted and effective cancer treatment. Su et al. introduced a positive feedback approach for cancer treatment to enhance therapeutic efficiency by maintaining continuous treatment (Su et al., 2020). They used black phosphorus nanoflakes and a transformation growth factor-β inhibitor encapsulated by the neutrophil membrane. The combination of PDT and PTT, along with the TGF-β inhibitor, led to acute local inflammation within the tumor, enhancing the administration of NPs through neutrophil membrane affinity. This combination led to robust immune activation within the tumor and successfully suppressed lung metastasis.

PTT and chemotherapy work well together and have many benefits over either treatment alone. According to several studies, PTT can improve drug delivery to tumors or cancer cells by strengthening vascular and membrane permeability (Fay et al., 2015). Additionally, PTT alone is more effective in treating primary tumors than disseminated metastatic tumors. Primary tumors and metastatic lesions can be managed using PTT and chemotherapy. Given such benefits, researchers have looked into employing CCNPs to deliver cytotoxic medications and photothermal agents to cure cancer simultaneously. The use of CCNPs to combine photothermal therapy (PTT) and chemotherapy has been widely investigated, with DOX being the most frequently used chemotherapeutic agent (Wang et al., 2018). The cancer cell membrane coating improved tumor delivery of DOX in all cases, resulting in successful combination therapy with PTT that decreased tumor growth. Membrane-wrapped NPs were co-loaded with DOX and photothermal agents (indocyanine green), and DOX was released into the tumor’s surroundings in a ‘bomb-like’ fashion (Zhang et al., 2018). In one instance, a hybrid membrane made of red blood cell (RBC) and B16-F10 mouse melanoma membranes was employed for enhanced immune evasion and tumor targeting (see Figure 3). DOX-loaded copper sulfide NPs encircled the hybrid membrane, and this system demonstrated synergistic effects with nearly 100% inhibition of tumor development (Chugh et al., 2021).

Figure 3. The hybrid membrane conceals DOX-loaded hollow CuS NPs (DCuS NPs) to develop DCuS@[RBC-B16] NPs. The synergistic effects of chemotherapy and photothermal therapy in the treatment of melanoma. Reprinted with permission from dongdong Wang, haifeng dong, meng Li, Yu cao, fan yang, kai Zhang, wenhao dai, changtao Wang, and xueji Zhang. ACS nano 2018 12 (6), 5241-5252 (Wang et al., 2018). Copyright 2018 American Chemical Society.

Combining chemotherapy with PDT has several benefits, including increasing the availability of ROS to initiate drug release and enable intracellular drug delivery, as well as producing hypoxia in the tumor region for activating encapsulated drugs (Fan et al., 2017). On the other hand, PDT has a drawback in that it is ineffective in hypoxic tumor areas because it depends on tumor oxygen. PDT can be used with medications not hampered by oxygen to treat tumors more thoroughly. In one case, tirapazamine was combined with a porphyrinic metal-organic framework (a PDT photosensitizer) as part of a dual PDT/chemotherapy regimen (Imran et al., 2017). Membranes derived from 4T1 breast cancer cells encased the drugs. After that, mice with orthotopic 4T1 breast cancer tumors received these agents. The ROS produced by the porphyrinic metal-organic structures during radiation exposure led to a localized hypoxic condition within the tumors. This encouraged TPZ activation, which increased the chemotherapeutic effect. There were few side effects because the treatment only worked when light had been present at the tumor location (Imran et al., 2017).

PDT was additionally utilized alongside starvation treatment in addition to chemotherapy. Starvation therapy involves administering glucose oxidase (GOx) to tumors, which converts glucose into gluconic acid and H₂O₂. During this process, the cells are deprived of glucose, a vital nutrient required for the growth of tumors. In one instance, hollow manganese dioxide (MnO2) NPs with a photosensitizer and GOx coating were used in a cascade reaction system. All components were then covered in B16-F10 cancer cell membranes (Pan et al., 2019). The MnO2 reactors were supplied to tumors and irradiated to generate oxygen continuously with the help of the transformation of glucose to singlet oxygen (Xie et al., 2019). This mechanism may help tumors with hypoxia-related problems and encourage starvation. Without PDT, starvation treatment through membrane-wrapped NPs was also investigated.

Cell membrane-based nanoparticles for cardiovascular therapy

The anticipated characteristics of cell membrane-coated NPs include precise localization to inflammatory regions, immune system avoidance, and high binding affinity to particular receptors or cells. CMCNPs are employed to replicate immune cells, platelets, and erythrocytes, which have been implicated in the growth of cardiovascular disorders. Rapamycin-loaded PLGA NPs coated RBC membranes were developed by Wang et al. Following therapy, the average area ratio of the plaque to the vascular lumen decreased from 47.95% to 31.34%, with the free drug group experiencing a significant reduction (from 47.95% to 42.42%), demonstrating the effectiveness of this nano platform in slowing the development of atherosclerosis (Wang et al., 2019). Shao et al. developed Janus-type polymeric micromotors covered in RBC membranes and composed of heparin and chitosan (Shao et al., 2018). This functional nanoparticle may aid in treating thrombosis because of its adequate mobility toward the thrombus in response to NIR radiation. The significant benefit of the red blood cell barrier is primarily utilized by the nanoplatforms covered above Immune escape and biocompatibility.

There are many traits that NPs coated with platelet membrane can display that are comparable to those of platelets, such as adhesion to damaged vasculature. This motivated Zhang et al. to develop PLGA NPs coated with platelet membranes, which showed specific adhesion to MRSA252 and rodent vasculature (Hu et al., 2015). By adding the proper loading agents to the interior PLGA center of these platelet membrane-coated nano-formulations, thrombus, arterial injuries, and sepsis could be treated. For instance, Wang et al. developed platelet membrane-coated PLGA NPs (PNPs/LBK) to treat thrombus. These PNPs/LBK contained lumbrokinase, a popular anticoagulant drug (Wang et al., 2020). Therefore, PNP/LBK exhibits enhanced thrombus targeting capacity with decreased risk of hemorrhages. ROS generation and tissue damage are encouraged when a thrombus forms because insufficient blood flow produces a hypoxic environment. Zhao et al. recently created H₂O₂-responsive platelet membrane-encased polymeric NPs (PNPArg) filled with argatroban to treat thrombus (Zhao et al., 2021). According to their strategy, the inner core of NPs is an H₂O₂ degradable polymer that can scavenge excessive ROS and function in conjunction with the anticoagulant drug argatroban to show excellent beneficial effects toward many thrombotic diseases.

CMCNPs are also advanced tools for diagnosis. Ma et al. developed a platelet membrane encapsulated NPs composed of Ce6 photosensitizer and upconversion NPs for precise localization and noninvasive photodynamic treatment of atherosclerosis (Ma et al., 2021). Platelets target foam cells and vascular endothelial cells, but they also have a strong attraction for activated neutrophils. With the help of platelets, neutrophils move into areas of the brain that are ischemic throughout acute ischemia stroke (AIS). ROS, known to be the primary source of reperfusion damage after AIS, is released by recruited neutrophils (Kolaczkowska and Kubes, 2013). Studies have suggested that reducing neutrophil influx may have therapeutic advantages (Schofield et al., 2013). These findings inspired Tang et al. to develop a novel platelet membrane-covered PLGA nanoplatform loaded with piceatannol and superparamagnetic iron oxide NPs (PTNPs) (Tang et al., 2019). By recognizing P-selectin (platelet) and PSGL-1 (neutrophil), the coated platelet membranes in their research enabled binding between NPs and neutrophils. Piceatannol, which was produced by the internalized nanoconstructs, reduced the amount of neutrophil infiltration in the areas of cerebral ischemia.

Bioactive lipid mediators, reactive oxygen species, and neutrophil extracellular traps (NETs) are released by activated neutrophils at the location of the inflamed lesion, causing inflammatory damage. Numerous cardiovascular treatments focus on inhibiting neutrophil infiltration or reducing inflammation caused by NETs to target neutrophils (Németh et al., 2020). Motivated by this idea, nanovesicles derived from neutrophil membranes containing Resolvin D2 (RvD2), a substance known to have anti-inflammatory properties. Their objective was to utilize these nanovesicles to treat brain injuries caused by postischemic strokes by suppressing the activation of endothelial cells and releasing cytokines and neutrophil infiltration into the cerebral ischemic lesion (Dong et al., 2019). Feng et al. successfully developed a mesoporous Prussian blue nanozyme (MPBzyme@NCM) with a membrane mimicking neutrophils (see Figure 4) (Feng et al., 2021). They found that MPBzyme@NCM can actively target the inflammatory brain microvascular endothelial cells, where NPs are then phagocytosed by microglia and ultimately removed by MPBzyme. Due to its ability to encourage microglia to polarize to M2 and decrease neutrophil migration, this nanoplatform can potentially treat ischemic stroke.

Figure 4. The illustration depicts membrane-coated nanozyme (MPBzyme@NCM) therapy for ischemic stroke, demonstrating its effectiveness in enhancing neuronal functional recovery. Reprinted with permission from Feng, L., et al., neutrophil-like cell-membrane-coated nanozyme therapy for ischemic brain damage and long-term neurological functional recovery. Acs nano, 2021. 15(2): p. 2263-2280 (Feng et al., 2021). Copyright 2021 American Chemical Society.

Macrophages are specialist cells identifying, destroying, and phagocytosing ‘invaders.’ Recent research has shown that macrophages are crucial in various cardiovascular-related procedures, such as cardiac regeneration, post-myocardial infarction remodeling, and atherosclerotic coronary artery (Khoury et al., 2021). By stimulating the CCR2-CCL2 axis, the macrophage membrane coating approach is frequently employed to increase the tumor-targeting ability. It additionally has the potential to target inflammatory lesion sites (Lim et al., 2016). This inspired Gao et al., who effectively coated NPs with macrophage-derived membranes for treating atherosclerosis (Gao et al., 2020). They created an inner core that responds to ROS to release the drug in their study rapidly. The macrophage membrane coating method helps target the lesion’s delivery by assisting NPs to escape the monocyte phagocyte system (MPS).

Additionally, pro-inflammatory mediators can be sequestered by macrophage membranes, which may limit local inflammation. The effectiveness of therapy against atherosclerosis can be significantly increased by combining medication and inflammatory cytokine clearance. To capitalize on macrophage membranes’ natural tendency for atherosclerotic plaque, Wang et al. developed a PLGA nanoplatform coated with macrophage membranes and loaded with the anti-inflammation drug Rapamycin (RAP) (Wang et al., 2021). Lipid deposition within plaques was reduced from 36.45% to 17.41% thanks to the remarkable therapeutic efficacy of this nanoplatform, outperforming the free RAP group (from 36.45% to 31.54%). Additionally, Xue et al. successfully developed macrophage membrane-encapsulated NPs carrying the miR-199a-3 anti-myocardial infarction (MI) agent (MMNPmiR199a-3p) for treating MI by using a cytokine neutralization method (Xue et al., 2021). In the research, macrophages were bioengineered to have higher IL-1 R, IL-6 R, and TNF-R expression levels. Because inflammatory mediators are neutralized, MMNP_miR199a-3p effectively inhibits the inflammatory response by being efficiently taken up by myocardial cells. In conclusion, macrophage membranes’ most frequently used applications for the treatment of CVDs are their ability to target the inflammatory lesion site and neutralize cytokines.

Cell membrane-based nanoparticles for infectious disease therapy

An infection that introduces pathogens into the body creates a complex immune response to eliminate the infection’s origin (Chaplin, 2010). The most prevalent diseases, mainly caused by bacteria, are typically treated with intensive antibiotic regimens. Researchers developed and tested a variety of novel technologies that seek to treat infections while using the fewest antibiotics possible due to the increase in antibiotic resistance throughout the years (Aslam et al., 2018). Invasive pathogenic bacteria have distinct relationships with their infectious microenvironment, which includes a variety of cell membranes; these relationships provide novel concepts for cell membrane-coating technology in antimicrobial therapy, similar to how cancer treatment functions. In the battle against bacterial infections, CMCNPs are also known to be effective in evading the immune system, attacking pathogenic bacteria, neutralizing toxins, toxoid vaccination, and prolonged circulation (Gao and Zhang, 2015). As an illustration, Zhang et al. described the RBC-nanogel system that can administer antibiotics to treat methicillin-resistant Staphylococcus aureus (MRSA) infection (Zhang et al., 2017).

Che et al. reported a biomimetic NPs system composed of polymeric NPs core and RBC membrane coating (Hu et al., 2013). When exposed to α-hemolysin from S. aureus, it was discovered that the nanosponge could impede the pore-forming toxin’s harmful effects on erythrocytes. Contrarily, neither polyethylene glycol-modified liposomes nor glycol-modified PLGA NPs could bind the α-hemolysin in adequate quantities to successfully block the α-hemolysin in this manner. Additionally, hemolysis was not halted by erythrocyte vesicles on their own, most likely due to their propensity to combine with healthy erythrocytes and propagate toxic damage. In vivo tests showed that nanosponges can neutralize bacterial exotoxins. Mice’s skin and underlying muscle tissue were severely harmed by the injection of α-hemolysin alone; nonetheless, the toxin was neutralized when combined with NPs, as the mice suffered minimal harm (Hu et al., 2013). Thamphiwatana et al. employed the macrophage membrane, which can bind LPS and reduce the amount of pro-inflammatory factors (Thamphiwatana et al., 2017). These NPs showed potent anti-inflammatory properties dose-dependent in vitro. NPs inhibited macrophage and endotoxin binding pathways as opposed to conventional endotoxin neutralizers, preventing harmful hyper-inflammatory responses linked to clinical toxicity. Pathogens attach to particular cells in the host when they spread infection. For instance, a variety of receptors are expressed by gastric epithelial cells, including integrin 1 (CD29), Lewis blood group antigens, and CEACAM5 (CD66e), which are capable of binding to Helicobacter pylori (Yuk et al., 2021; Safarov et al., 2019). The researchers enclosed Clarithromycin (CLR) in PLGA NPs and covered it with membranes from human gastric epithelial cells. This AGS-coated nanoparticle (AGS NP) targets H. pylori more effectively than uncoated NPs. During an experiment on treating H. pylori in live mice, the number of H. pylori bacteria in the stomach of mice treated with CLR loaded in AGS-NPs was twice lower than those treated with NPs that lacked a membrane coating. Additionally, the number of H. pylori bacteria in the stomach of those mice treated with CLR loaded in AGS-NPs was three times lower than those treated with free CLR (Angsantikul et al., 2018).

Furthermore, the bacteria may use various mechanisms to engage with platelets, including binding directly with bacterial surface proteins or connections with plasma bridging molecules. For instance, MRSA can bind to platelet membranes and avoid being eliminated by the immune system. Researchers discovered that when using platelet membrane-coated NPs (PNPs), the binding capacity of vancomycin-loaded PNPs to MRSA was 12 times higher than that of bare NPs. The potent combination markedly boosted bactericidal potency in a mouse model of MRSA infection, showing six times more efficiency than free vancomycin (Hu et al., 2015). In addition, bacterial stimulus can increase the expression of PAMPs, particularly the toll-like receptors, TLRs, which can enhance the binding capacity of microbial molecular patterns and PAMPs (Kawai and Akira, 2011). Designing antimicrobial strategies that utilize the infected microenvironment enables the targeted release of drugs specifically at the infection site. Supramolecular gelatin NPs (SGNPs) coated in RBC membranes were created by Li et al. (Figure 5) (Li et al., 2014). The RBC membrane lengthens the time the NPs remain at the infection site, increasing their capacity to escape the immune system. CMCNPs are more successful because they can target bacteria and the infection microenvironment. This strategy can also lessen the harmful effects of antibiotics on the body and delay the emergence of resistant pathogenic bacteria (Li et al., 2014).

Figure 5. (a) The creation of SGNPs with a layer of RBC membrane coating enclosed in vancomycin (VanSGNPs@RBC). (b) adaptive and multipurpose van⊂SGNPs@RBC in the therapy of bacterial infections are shown schematically. Adapted with permission from Li, L.-L. et al., core–shell supramolecular gelatin NPs for adaptive and ‘on-demand’ antibiotic delivery. ACS nano, 2014. 8(5): p. 4975-4983 (Li et al., 2014). Copyright 2014, American Chemical Society.

A crucial defense against bacterial illnesses is vaccination. Due to the unique characteristics of NPs and cell membranes, a few CMCNP vaccines have been investigated to avoid infections (Angsantikul et al., 2017). The ability of NPs to be quickly taken up by cells allows antigens affixed to them to be efficiently taken up and processed by antigen-presenting cells. In addition, the antigen junctions on the nanoparticle surface exactly mimic how pathogenic antigens naturally present themselves because the cell membrane vesicles themselves are antigens or can adsorb multiple antigens. Different infectious organisms can be used to make NPs and cell membranes as vaccine delivery vehicles (Angsantikul et al., 2017). Proteins and carbohydrates comprise the bacterial outer membrane vesicle (OMV), which has the same innate immunostimulatory effects as bacteria (Gerritzen et al., 2017). Some of these cysts were utilized in clinical bacteria pathogen protection, like a meningococcal vaccine, which has been shown to activate the host immune response (Holst et al., 2013). To further increase the bacterial OMV vaccine’s efficacy, a platform for imitating bacterial NPs was developed that encapsulates the gold NPs (BM-AuNPs) with bacterial membranes (Gao et al., 2015). Using AuNP backbones, vesicles are guaranteed to be uniform in size and exhibit excellent vesicle durability. Because of this, the BM-AuNPs were significantly more robust in bio-buffered solutions, and employing OMVs makes it possible for the reliable release of important immune determinants like PAMPs. In rodents, subcutaneously injected BM-AuNPs caused dendritic cells to activate and mature quickly. Furthermore, BM-AuNPs inoculation produced more potent and durable antibody reactions than OMVs alone. These results imply that coating synthetic NPs with bacterial OMVs may provide helpful information for developing an extremely potent and secure antibacterial vaccine (Gao et al., 2015).

As a result of their characteristics, like toxin adsorption and antigen distribution via membrane surface, CMCNPs can help create antitoxin vaccines. RBC-coated NPs offer a novel strategy for developing multi-antigen vaccines because they can absorb toxins and encourage high immunogenicity without using adjuvants. To enable them to absorb all membrane-associated toxins, RBC-coated NPs were treated with crude proteins obtained from MRSA culture supernatant by Wei et al. (Wei et al., 2017). The outcomes demonstrated the simultaneous adsorptive binding of numerous toxic proteins. Furthermore, hSP (hemolytic secreted protein from MRSA strain USA300) is inhibited from hemolysis and cytotoxicity by these NPs, which are less harmful than standard heat-inactivated hSP because they can capture and neutralize a variety of exotoxins. It was demonstrated that these NPs could concurrently generate antibody titers against the retained toxins when used as a multiantigen formulation. This ability was superior to that of traditional heat-inactivated hSP. In a cutaneous infection model of MRSA, this approach significantly reduced lesion growth and bacterial population while providing substantial vaccination protection against live bacteria. In comparison, the heat-treated MRSA protein showed significant cytotoxicity, and after 4 hours of boiling, it still maintained about half of its hemolytic activity (Wei et al., 2017).

Cell membrane-based nanoparticles for viral infections

Cell membrane-based and coated nanovesicles can function as nanodecoys to trap and strip pathogens of their infectious properties (Rao et al., 2020). Several studies have examined the possible benefits and demonstrated their efficacy in treating diseases like HIV, Zika, and Hepatitis B (Rao et al., 2018; Wei et al., 2018; Liu et al., 2018). Here, the pathogen can disguise itself as a target cell membrane-coated nanoparticle and bind to its native target cell. Rao et al. have successfully devised a biomimetic nano decoy (ND) capable of effectively capturing the Zika virus (ZIKV), redirecting it away from its intended targets, and impeding its ability to cause infection (Rao et al., 2018). The ND, consisting of a gelatin NP core enveloped by mosquito medium host cell membranes, demonstrates efficient adsorption of ZIKV and inhibition of ZIKV replication in cells sensitive to ZIKV (see Figure 6). The trapping of ZIKV by NDs effectively inhibits the transmission of ZIKV across physiological barriers, thereby reducing the occurrence of ZIKV-induced fetal microcephaly. This study provides novel perspectives on establishing reliable and efficient measures for safeguarding against viruses that pose a significant risk to public health. This immobilization eliminates its virulence by preventing the virus from attaching to host target cells. Other investigations employing CD4+ T cell plasma to cloak polymeric NPs in HIV models have described an identical phenomenon (Wei et al., 2018; Zhang et al., 2020). Cell membrane-coated NPs can serve as effective platforms for delivering antigens to antigen-presenting cells (APCs) and can be utilized as multivalent nanovaccines. Through interacting with mannose receptors, ligands like mannose, for example, can enhance the targeting of NPs to APCs. In a recent study, mannose-modified RBC-derived membranes were used to coat chitosan cores loaded with plasmid DNA (pDNA), boost the effectiveness of transfecting APCs with antigen-encoding pDNA, and activate potent immune responses with preventive benefits against fish viral disease (Zhang et al., 2020).

Figure 6. A schematic representation of an ND that exhibits the capability to adsorb the ZIKV. (b) TEM image depicting a solitary ND demonstrating the process of adsorption of the ZIKV. Red arrows denote the presence of ZIKV. Reprinted with permission from lang Rao et al., nano letters 2019 19 (4), 2215-2222 (Rao et al., 2018). Copyright 2019 American Chemical Society.

Cell membrane-based NPs for COVID-19 treatment

SARS-CoV-2 enters the bloodstream and interacts with protein receptors on target cells to make it more pathogenic. Because of this, traditional treatments are also appropriate in this circumstance. Technically speaking, the pathogen and membrane’s interaction is similar to that of more well-known infectious illnesses. In response to this, a new strategy involved the development of nanovesicles based on cell membranes that can act as virus-trapping cells and nano-decoys for cytokine neutralization and virus immobilization (Rao et al., 2020). The genetic modifications were made to human embryonic kidney 293 T cells so that the ACE2 protein could be seen. Next, vesicles from cell membranes with ACE2 attached were isolated and combined with human myeloid mononuclear THP-1 cells enriched with cytokine receptors. These THP-1 cells were derived from human monocyte mononuclear cells as precursors while maintaining the source cells’ original biological properties, structure, and orientation.

Furthermore, the potential of nano decoy-assisted COVID-19 therapeutics was highlighted by demonstrating their ability to alleviate acute pneumonia in mice models of acute lung inflammation. This suggests promising applications for the treatment of COVID-19 (see Figure 7). These SARSCoV-2-binding and -immobilization nanovesicles, derived from cell membranes, effectively demonstrate the multiple applications of biomimetic nanosystems through interactions with membrane-exposed cytokine receptors (Rao et al., 2020).

Figure 7. This figure presents a schematic representation of nanodecoys utilized in combating COVID-19. The process involves the development of nanodecoys through the fusion of cellular membrane nanovesicles obtained from genetically modified 293 T/ACE2 and THP-1 cells. The nanodecoys, which exhibit a high abundance of cytokine receptors and ACE2, compete with host cells, protecting against COVID-19. This protective mechanism involves the neutralization of SARS-CoV-2 (B) as well as inflammatory cytokines like GM-CSF and IL-6 (C). reproduced from reference (Rao et al., 2020) under Creative Commons Attribution license 4.0 (CC by).

A different study found that nanovesicles derived from the membranes of ACE2-rich human embryonic kidney-293 T cells could bind to the spike protein of SARS-CoV-2 through biocompetitive inhibition. Consequently, the virus was neutralized and kept from penetrating host cells, particularly renal tubular epithelial cells, and entering their cytoplasm (Wang et al., 2021). A separate study showed that the corticosteroid dexamethasone-loaded leukosomes (LKs), vesicles made from leukocytes, significantly improved the drug’s pharmacokinetics. In addition, they were able to mitigate the inflammatory response triggered by SARS-CoV-2 in a mouse model of lipopolysaccharide-induced endotoxemia (Molinaro et al., 2020). Creating dexamethasone-loaded leukosomes (LKs) utilized mouse macrophage J774 cell lines. These vesicles had an aqueous center that helped dexamethasone dissolve and a shell made of a macrophage cell membrane. The dexamethasone-loaded LKs significantly decreased the generation of pro-inflammatory cytokines and increased the overall survival of mice models of inflammation. The LKs also have anti-inflammatory properties because they elevate levels of anti-inflammatory cytokines while lowering levels of pro-inflammatory cytokines (Molinaro et al., 2019).

An NPs core can confer excellent stability in biological settings than a cell membrane vesicle alone. Researchers utilized a similar approach by incorporating polymeric NP cores. PLGA cores were encircled with nanosponges made of membranes derived from human cells. These membranes come from cells that SARS-CoV-2 usually targets. The hypothesis was that once the virus adheres to the nanosponges, it becomes immobilized and deactivated and can no longer bind to its cell targets (Zhang et al., 2020). Human lung epithelial type II or macrophage cell membranes were used to create nanosponges. The findings reveal that although both nanosponges were effective against COVID-19, those derived from macrophage cell membranes might have more potential as a treatment. This is probably because of their capacity to lower the body’s viral load, inhibit viral activity, and perform intrinsic immunological tasks. This may help lessen the abrupt and severe inflammatory response that develops in the later phases of COVID-19. Concerning preclinical safety, following intratracheal administration of the nanosponges to rodents, neither hemotoxicity nor abnormal immune cell infiltration were found (Zhang et al., 2020).

The viral spike protein that triggers COVID-19’s pathogenicity can be divided into S1 and S2 subunits after degradation, with the S1 subunit responsible for recognizing host receptors and the S2 subunit causing viral fusion into the cytoplasm. The S1 enters the cells by binding to ACE2 (Wang et al., 2021; Lei et al., 2020). To avoid SARS-CoV-2 infection, researchers have created cell membrane-coated NPs employing the human embryonic kidney-239 T cells membrane that excessively produces the human ACE2 (HEK-293 T-hACE2). These NPs work by competitively binding with the S1 proteins, preventing the virus from binding to the cell membrane and entering targeted cells. According to the study, as anticipated, the biomimetic nanocarriers could adsorb the SARS-CoV-2 S pseudovirons on their surface. This, in turn, prevented viral entry into the cytoplasm and effectively neutralized its virulence (Fang et al., 2018; Wang et al., 2021).

Cell membrane-based nano-particles for autoimmune diseases

One of the leading causes of death worldwide is autoimmune diseases that occur when the body fails to recognize its cells and attacks them (Kuai et al., 2019). In recent years, cell membrane-coated NPs have emerged as a potential immunotherapy to target autoimmune diseases. This approach involves using the NPs as decoys to divert the immune system’s attention away from attacking healthy cells. For example, a group of researchers led by Jonathan A. Copp developed erythrocyte membrane-coated PLGA NPs to target anti-erythrocyte antibodies (Zhang et al., 2018). Contrary to traditional immunotherapy, biomimetic NPs could halt disease progression with the fewest side effects by focusing on disease-causing antibodies rather than suppressing healthy lymphocytes or immune effector cells. Unlike the control group, rodents treated with RBC-ANS had autoantibodies that were well-tolerated by the body and did not worsen the humoral immune response to NPs-associated membrane antigens. ITP is similar to AIHA in that it is attributed to the body’s harmful anti-platelet antibodies, which reduce platelet count and elevate bleeding.

Additionally, nonspecific immunotherapy frequently had more severe adverse effects than the illness. To precisely eliminate anti-platelet antibodies, Xiaoli et al. employed platelet membrane-coated NPs (Wei et al., 2016). These NPs have been shown to precisely and consistently bind to anti-platelet antibodies in both in vivo and in vitro experiments, showing that they can serve as an alternative target of anti-platelet antibodies for treating ITP and protecting circulating platelets (see Figure 8). In standard ITP mouse models, platelet membrane-coated NPs therapy was superior to control groups in preventing prevalent immune side effects and reducing ITP symptoms. Cell membrane-coated NPs have the potential to be utilized as hopeful and effective biomimetic decoys to treat autoimmune diseases.

Figure 8. The illustration shows the structure of platelet membrane-coated nanoparticles (PNPs) used in treating immune thrombocytopenic purpura. PNPs are produced by extracting plasma membrane from platelets and coating them on PLGA nanoparticle cores. PNPs neutralize pathogenic autoantibodies, preventing their circulation and promoting healthy platelet survival. Reprinted with permission from Wei, X., et al., nanoparticles camouflaged in platelet membrane coating as an antibody decoy for the treatment of immune thrombocytopenia. Biomaterials, 2016. 111: p. 116-123 (Wei et al., 2016). Copyright elsevier ltd 2016.

Despite the paucity of research in this area, some researchers have demonstrated the therapeutic potential of cell membrane-based biomimetic NPs in conditions like rheumatoid arthritis, type II immune hypersensitivity responses, and inflammatory bowel disease (IBD). These biomimetic NPs have been demonstrated to imitate native cells that can reduce inflammation and heal tissue damage in these disease conditions by acting as binding decoys for processes that initiate the chronic inflammatory state. To take advantage of the processes of T cell recruitment during the progression of IBD, engineered leukocyte membranes imitating NPs were developed to overexpress a4b7, a critical integrin protein on T-lymphocytes, to attach to inflamed mucosal tissue (Sushnitha et al., 2020). These ‘specialized leukosomes’ showed stronger attachment to inflamed endothelial due to this overexpression. These biomimetic NPs enhanced crypt structure, decreased CD45+ immune cells and inhibited edema in DSS-induced IBD mice (Corbo et al., 2017). These NPs, therefore, served as antagonistic ligands for receptors that would otherwise have adversely overstimulated the immune response. RBC-mimicking NPs were used to show this method for removing pathological antibodies. More specifically, these RBC-based biomimetic NPs acted as binding decoys for antibodies that generally adhere to native RBCs and mark them for extravascular hemolysis (Copp et al., 2014). These RBC-NPs assisted mice with an induced anemia model in getting their hemoglobin and RBC counts back to normal. The RBC count was reduced by 60% in mice not administered with the NPs, and the hemoglobin levels dropped twice (Table 1).

Finally, it has been demonstrated that neutrophil-mimicking NPs have significant therapeutic benefits in treating rheumatoid arthritis. In this investigation, neutrophil membranes were fused with NPs to evaluate the NPs’ capacity to block the detrimental immune response brought on by the development of this illness (Zhang et al., 2018). Similar to the instances given earlier, these NPs served as a decoy for biological molecules targeting neutrophils. This is crucial for treating rheumatoid arthritis because decreasing neutrophil recruitment to the synovial fluid has been demonstrated to help reverse the disease (Wright et al., 2017). These NPs reduced joint degeneration and suppressed proinflammatory mediators in two murine models of arthritis. These findings show the adaptability of biomimetic NPs in focusing on and improving the underlying mechanisms that underlie and promote a variety of autoimmune diseases (Table 2).

Table 2. Summary of recent studies in nanoparticle research.

Author	Nanoparticle Type	Application	Toxicity Insights	Efficacy in Cancer Treatment	Biogenic Green Materials	Alzheimer’s Disease Applications
Sargazi et al. (2022)	Gold nanoparticles	Cancer therapy	Low toxicity in vitro, in vivo	Enhanced tumor targeting	Green synthesis of gold NPs	Early diagnosis and drug delivery
Gao et al. (2013)	Liposomal nanoparticles	Drug delivery	Liposome biocompatibility	Improved drug delivery	–	–
She et al. (2018)	Mesoporous silica NPs	Drug delivery	Controlled release profiles	Targeted drug delivery	–	–
Jeon et al. (2021)	Iron oxide nanoparticles	Imaging	MRI contrast agent safety	Magnetic targeting	–	–
Kortel et al. (2020)	Graphene quantum dots	Imaging/Therapy	Low cytotoxicity	Drug delivery, photothermal therapy	–	Alzheimer’s biomarker detection
Wypij et al. (2021)	Green-synthesized silver NPs	Anticancer	Biocompatibility, eco-friendliness	Antiproliferative effects	Green synthesis methods	–
Saha et al. (2023)	Biogenic copper NPs	Antimicrobial	Low toxicity, antimicrobial activity	–	Green synthesis of copper NPs	–
Ahmed et al. (2022)	Green-synthesized nanoparticles	Various	Biocompatibility, eco-friendliness	Application-specific effects	Green synthesis approaches	–
Zhang et al. (2022)	Lipid-based nanocarriers	Gene therapy	Low immunogenicity	Targeted gene delivery	–	–
Gagliardi et al. (2021)	Polymeric nanoparticles	Drug delivery	Polymer biodegradability	Controlled drug release	–	–

Conclusion

NPs with cell membrane coatings can significantly improve the efficacy of present nanoparticle systems in managing various diseases. They blend distinctive capabilities in different cell types and adaptable designs drawn from multiple cores, which might create new targeting tactics. The remarkably extended circulation duration found after coating with cell membranes is an exciting feature of these strategies. Identical to the parent cells from which they are produced, such coated NPs are recognized as ‘self’ by the body’s immune system, which minimizes elimination by the RES system. Extravasation, chemotaxis, and particular cell-to-cell interactions can all be made possible by the inherent targeting capabilities of cell membranes, which are similar to exosomes. More specialized cell membrane coatings could be created to accomplish the desired therapeutic effects as research on cell function progresses.

Cell membrane-coated NPs may play a part in cancer immune modulation and serve as carriers for targeted drug release. Zhang et al. recently studied and reported using red blood cell-coated NPs to deliver bacterial-derived antigens for anti-virulence vaccination (Li et al., 2018). According to the research, attaching cancer-related antigens to cell membrane-coated NPs might improve immune recognition of cancer. In addition, the formation of cell membrane-coated NPs that may elicit an immune response and possibly aid postoperative immunotherapy may be made possible by isolating the particular cancer cell membrane from tumor resection.

Cell membrane-coated NP research and development have advanced significantly. However, the field is still fresh, and several issues must be resolved before they can be applied in therapeutic settings. First, there are few sources for cell membranes; aside from RBC membranes, most are obtained from cell lines and require several processes. This process is complicated, and yields of CMCNPs are low. Therefore, there is an urgent need to simplify and expand the preparation process of CMCNPs for clinical studies. Secondly, more research is needed to fully realize the potential of this strategy because some aspects are still not fully known. For instance, numerous proteins found on cell membranes have not yet been thoroughly studied. Some of these proteins are responsible for targeting, while others may trigger immune responses. Identifying helpful proteins and removing unwanted ones will undoubtedly enhance the performance of CMCNPs in cancer therapy. Thirdly, as opposed to synthetic materials, it is difficult to regulate the quality and ensure the safety of cell membrane-coated NPs. A change in emphasis from discovery to process development and multidisciplinary collaboration is required to address these problems. In conclusion, the development of biomimetic design has revolutionized how different illnesses are treated with nanomedicine. Treatment methods using cell membrane-based NPs will progress with the development of more potent and creative strategies.

Authors contribution

ML, writing the initial draft of the manuscript; QG, Organizing the manuscript and final review of the manuscript; CZ, finalizing the manuscript; ZZ, reviewing and finalizing the manuscript. All the authors approved the manuscript to be published; all authors agree to be accountable for all aspects of the work. All listed authors meet the criteria for authorship as per the ICMJE guidelines.

Disclosure statement

All the authors declare that they have no competing interests.

Data availability statement

There is no supplemental data in this paper. All information is available in the manuscript.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.