Advances in cell membrane-based biomimetic nanodelivery systems for natural products

Abstract

Active components of natural products, which include paclitaxel, curcumin, gambogic acid, resveratrol, triptolide and celastrol, have promising anti-inflammatory, antitumor, anti-oxidant, and other pharmacological activities. However, their clinical application is limited due to low solubility, instability, low bioavailability, rapid metabolism, short half-life, and strong off-target toxicity. To overcome these drawbacks, cell membrane-based biomimetic nanosystems have emerged that avoid clearance by the immune system, enhance targeting, and prolong drug circulation, while also improving drug solubility and bioavailability, enhancing drug efficacy, and reducing side effects. This review summarizes recent advances in the preparation and coating of cell membrane-coated biomimetic nanosystems and in their applications to disease for targeted natural products delivery. Current challenges, limitations, and prospects in this field are also discussed, providing a research basis for the development of multifunctional biomimetic nanosystems for natural products.

Keywords:

• active components
• natural products
• cell membrane-based
• biomimetic
• nanosystems

1. Introduction

Natural products play a vital role in the prevention and treatment of diseases, such as cancer, Alzheimer’s disease, Parkinson’s disease, and other pathological conditions. Natural products have been used for a long time since ancient times, which is directly attributable to the therapeutic values and lower adverse side effects compared to modern medicine. Its efficacy relies on the use of multiple active components, including paclitaxel (PTX), curcumin (Cur), gambogic acid, resveratrol, triptolide and celastrol (Liu et al., 2020b; Zheng et al., 2022), which show promising anti-inflammatory, antitumor, anti-oxidant, and other pharmacological activities (Table 1 and Figure 1) (Kocaadam and Sanlier, 2017; Hatami et al., 2020; Huang et al., 2020a; Viegas et al., 2020; Kaur et al., 2022; Li et al., 2022a). However, the development and application of these active components is limited due to poor solubility, low bioavailability, short half-life, and instability in biological environments (Puglia et al., 2017).

Figure 1. The active components of natural products mentioned in this review. Original image created by author(s).

Table 1. Origin and biological activities of active components discussed in this review.

Active ingredient	Classification	Plant origin	Activities	Ref.
PTX	Diterpenoid alkaloids	Bark and wood of Pacific yew	Antitumor	Li et al. (2022a)
Cur	Diarylheptanoid	Rhizomes of herbs of the ginger family	Anti-oxidant, anti-inflammatory, antitumor, neuroprotective	Kocaadam and Sanlier (2017)
Gambogic acid	Caged xanthone	Brownish/orange gamboge resin of the Garcinia hanburyi tree	Antitumor	Hatami et al. (2020)
Resveratrol	Non-flavonoid phenolic	Skin of red grapes, mulberries, peanuts, pines, and Polygonum cuspidatum weed root extracts	Anti-oxidant, anti-inflammatory, antitumor, neuroprotective, antibacterial	Kaur et al. (2022)
Triptolide	Epoxy diterpene lactone	Tripterygium Wilfordii Hook F.	Anti-inflammatory, antitumor	Viegas et al. (2020)
Celastrol	Pentacyclic triterpenoid		Anti-oxidant, anti-inflammatory, antitumor	Huang et al. (2020a)

In recent decades, nanodelivery systems such as liposomes, solid lipid nanoparticles, nanoemulsions, micelles and polymer nanoparticles have been widely used to overcome these challenges(Dadwal et al., 2018; Patra et al., 2018; Swierczewska et al., 2018; Liu et al., 2023b). Compared to modern medicine, nanocarriers offer better solubility, pharmacokinetics, biodistribution, bioavailability and stability as well as lower toxicity. In addition, they protect drugs from degradation and inactivation and prolong their time in circulation through sustained release (Din et al., 2017; Crintea et al., 2022). However, they still suffer from fast elimination, low target specificity, and poor tumor permeability. Modifying nanoparticles with polyethylene glycol (PEG) shells can prolong their circulation and reduce their toxicity, but also impede their cellular internalization (Gabizon and Martin, 1997; Harris et al., 2001; Karakoti et al., 2011; Sanchez Armengol et al., 2022). In addition, nanodelivery systems modified with ligands such as antibodies, peptides and folic acid may be easily recognized by the mononuclear macrophage system, which removes them from the circulation and inhibits targeted drug delivery (Bajracharya et al., 2022; Wang et al., 2020a).

Biomimetic nanocarriers have recently emerged as novel nanomaterials with greater ability to target cells and to evade immune responses. These nanoparticles are cloaked in the ‘camouflage’ of membranes derived from red blood cells (RBCs), white blood cells (WBCs), platelets or cancer cells, the resulting camouflaged nanoparticles attain special functions including immune escape, longer circulation times, excellent biosafety and homologous targeting ability (Jin et al., 2018; Lu et al., 2023). These membranes can even be modified with functional groups to strengthen drug efficacy, and they can be administered in combination with other treatments, such as magnetic hyperthermia, photodynamic therapy (PDT), and acoustic dynamic therapy.

In this review, we summarize the developments in biomimetic nanodelivery systems for natural products over the past five years, focusing on nanopreparations coated with different cell membranes (Figure 2). This study may serve as a reference for the future application of cell membrane biomimetic technology in the delivery of active but insoluble natural products.

Figure 2. Cell-derived biomimetic nanocarriers used in disease treatment. Original image created by author(s).

2. Experimental basis of cell membrane-based biomimetic nanoparticles

2.1. Preparation of cell-derived membrane

The first step in the preparation of biomimetic nanopreparations is the extraction and purification of the cell membrane, both of which need to be prudently treated to preserve the structure of the cell membrane and the activity of surface proteins (Liu et al., 2019d).

Above all, the cell membrane was extracted by hypotonic cracking, repeated freeze-thawing and mechanical crushing. The principle of hypotonic lysis is that cells will swell and rupture under low osmotic pressure to release the contents, which is widely used in the extraction of erythrocyte membrane (Feng et al., 2022; Xu et al., 2023a, 2023b). Repeated freeze-thawing involves freezing cells at low temperatures and thawing them repeatedly at room temperature to remove the contents (Ji et al., 2023; Li et al., 2023b). However, freezing and thawing can potentially cause damage such as reduced protein activity. Cells are broken by mechanical crushing due to the intense ultrasonic shock wave and shear stress (Fan et al., 2021; Wu et al., 2023). This method is efficient but generates large amounts of heat, resulting in the inactivation of cell membrane proteins. Hence, the corresponding cooling measures should be considered. At present, the combined use of these methods can yield satisfactory results.(Chu et al., 2023; Liu et al., 2023c; Ma et al., 2023; Xie et al., 2023). For example, neutrophils were first treated by hypotonic lysis and later treated using a homogenizer. Glioma cells and stromal cells were first treated by hypotonic lysis followed by repeated freeze-thawing treatment. Consequently, the cell membrane proteins were preserved and the nanopreparations were successfully functionalized.

Differential centrifugation is generally used to purify cell membranes (Du et al., 2023; Li et al., 2023a). Some researchers also use sucrose density gradient centrifugation or ultrafiltration to purify cell membranes (Lai et al., 2015; Gao et al., 2020b; Xie et al., 2023). The cell membrane vesicles were resuspended in PBS and saved at −80 °C until use.

2.2. Methods of membrane-preparation fusion

There are three main methods of membrane-preparation fusion, including physical extrusion, sonication, and microfluidic electroporation. Extrusion is the process of repeatedly mechanically pushing a nanopreparation through a 400 nm, 200 nm, and 100 nm polycarbonate porous membrane to fuze it to the cell membrane (Huang et al., 2023b; Ying et al., 2023). The method is very robust in terms of repeatability and is one of the most used methods for preparing membrane camouflaging nanopreparations. The primary drawback of using this method for time-consuming and labor-intensive, thus cannot achieve batch preparation. Inspired by the merit of simple and efficient operation, researchers increasingly use sonication to generate cavitation bubble for the spontaneous fusion of nanopreparations and cell membrane-derived vesicles (Liu et al., 2019c). This technique has the added benefit of losing less material than physical extrusion. However, the size of biomimetic nanopreparations prepared by ultrasonic method is not uniform, and the damage of heat generation on the activity of membrane proteins during ultrasonic process is irreversible. Lastly, a relatively new approach to enable membrane coating is to employ microfluidic electroporation (Rao et al., 2017; Liu et al., 2019a). This fabrication technique uses electric pulses to create temporary hydrophilic pores in the cell membrane so that the nanomaterials can successfully enter the cell membrane. The bionic nanomaterials obtained have uniform particle size and are efficient and can be mass-produced. However, problems such as high cost and lack of specifications and standards for core technologies need to be addressed.

2.3. Characterization of cell membrane-based biomimetic nanoparticles

To ensure the logic and effectiveness of the membrane coating process design, it is necessary to in vitro verify the structure, morphology, physical and chemical properties, and integrity of the surface proteins of the cell membrane after the successful preparation of biomimetic nanopreparations. The core-shell structure of membrane biomimetic nanopreparations can be directly observed using a transmission electron microscope or scanning electron microscope. The size and potential of membrane-coated nanopreparations can be determined using dynamic light scattering and zeta potential, respectively. The size of the hydrated particles and the electronegativity of the nanoparticles increased when membrane-encapsulated and coincided with the zeta potential of the membrane surface. The integrity of membrane surface proteins was confirmed using sodium dodecyl sulfate-polyacrylamide gel electrophoresis on intact cells, isolated cell membranes, and protein bands coated with nanoparticles. And a Western blot was used to examine the distinctive proteins on the cell membrane. Fluorescent dyes have recently been used to confirm that membrane-mimicking nanopreparations have been successfully prepared (Liu et al., 2019b). Fluorescent dyes were employed to identify the cell membrane and the nanoparticle in turn, and then the membrane-coated nanoparticles were observed and analyzed using laser scanning confocal microscopy.

3. Cell membrane-based biomimetic nanoparticles for natural products

3.1. RBC membranes

RBCs, the most abundant cells in the human body, circulate in the blood for up to 120 days and are considered ideal carriers for various bioactive compounds such as enzymes, drugs, proteins, and macromolecules. Mature RBCs lack a nucleus and various organelles, which makes their extraction and purification particularly easy (Pierige et al., 2008; Lanao et al., 2020). The long-term circulation of RBCs is mediated by several membrane proteins, including integrin-associated protein (CD47), C8-binding protein, homologous restriction protein, and decay acceleration factor; these proteins play a key role in the evasion of immune defenses, including the complement system. CD47 also serves as a ‘do-not-eat-me signal’ that interacts with the glycoprotein signal-regulatory protein-α (SIRP-α) on macrophages to prevent RBCs from being cleared by the immune system (Barclay, 2009; Barclay and Van den Berg, 2014; Villa et al., 2016). Since cell membranes inherit the properties of their parent cells, polymer-based nanodelivery systems coated with RBC membranes (RBCMs) have been widely explored in recent years (Table 2) (Hu et al., 2011), and this work has demonstrated their potential for preventing nanoparticle clearance by the human immune system and improving targeting efficiency for cancer treatment.

Table 2. Examples of drug-loaded nanoparticles coated with red blood cell membranes for disease treatment.

Preparation method	Nanosystem	Cargo	Membrane modification	Combined therapy	Treatment model	Disease	Advantages	Ref.
Ultrasonication	–	Cur	–	Chemotherapy	L929 fibroblasts	Wound healing	Promotes cell attachment and proliferation.	Safarpour et al. (2022)
Mechanical extrusion	Nanomicelles	Cur/angelica polysaccharide	–	Chemotherapy	HepG2/MDA-MB-231 cells; HepG2 tumor-bearing nude mice	Hepatocellular carcinoma	Favorable drug-loading capacity; biocompatibility; enhanced synergistic antihepatoma effects.	Guo et al. (2021)
Ultrasonication	–	Celastrol	–	Chemotherapy	APAP‑induced acute liver injury model	Drug-induced liver injury	Lower cytotoxicity; well-sustained release effect.	Zheng et al. (2023)
Mechanical extrusion	Nanostructured lipid carriers	PTX	–	Chemotherapy	NCI-H1299/S180 cells; S180 tumor-bearing mice	Cancer	Enhanced cellular uptake in cancer cells; evasion of macrophages, prolonging circulation in the blood.	Zhou et al. (2021)
Ultrasonication	PEG nanocrystals	PTX	–	Chemotherapy	4T1/3T3 cells; 4T1 xenografted BALB/c mice	Cancer	Strong cellular cytotoxicity; good antitumor efficacy in tumor-bearing animals.	Zhai et al. (2020)
Ultrasonication	PLGA nanoparticles	PTX/triptolide	–	Chemotherapy	BGC-823/SGC-7901 cells	Gastric cancer	Prolonged blood circulation through evasion of macrophages and enhanced cytotoxicity.	Wang et al. (2021b)
Ultrasonication/Mechanical extrusion	PLGA Nanoparticles	Cur	–	Chemotherapy	H22/L929 cells; H22 tumor-bearing mice	Cancer	Enhanced antitumor efficacy; reduced systemic toxicity.	Xie et al. (2019)
Ultrasonication	PCL-PEG nanoparticles	Resveratrol	–	Chemotherapy	HT29 cells; xenograft model	Colorectal cancer	Escape from the monitor of immune cells and enhances biocompatibility.	Zhang et al. (2022)
Mechanical extrusion	–	PTX	Anti-EGFR-iRGD protein	Chemotherapy	MKN45 cells; tumor-bearing BALB/c nude mice	Gastric cancer	Enhanced drug accumulation; improved tumor suppression.	Chen et al. (2018a)
Mechanical extrusion	PLGA Nanoparticles	Gambogic acid	Anti-EGFR-iRGD protein	Chemotherapy	HT-29 cell lines; Caco-2 tumor-bearing nude mice	Cancer	Improved targeting ability; high antitumor efficiency; reduced side effects; in vivo safety.	Zhang et al. (2018b)
Ultrasonication/Mechanical extrusion	PLGA nanoparticles	Cur	T807	Chemotherapy	HT22 cells; mice with Alzheimer’s disease	Alzheimer’s disease	Decrease in intracellular phosphor-tau; suppression of neuronal death; scavenging of reactive oxygen species.	Gao et al. (2020a)
Mechanical extrusion	Human serum albumin nanoparticles	Cur	T807; TPP	Chemotherapy	HT22 neuronal cells; mice with Alzheimer’s disease	Alzheimer’s disease	Crossing of blood-brain barrier; specific binding to neuronal cells; mitochondrial targeting.	Gao et al. (2020c)
Mechanical extrusion	Nanostructured lipid carriers	Resveratrol	RVG29; TPP	Chemotherapy	HT22/bEnd.3 cells; mice with Alzheimer’s disease	Alzheimer’s disease	Crossing of blood-brain barrier; specific binding to neuronal cells; mitochondrial targeting.	Han et al. (2020b)
Ultrasonication/Mechanical extrusion	nanocrystals	Cur	RVG29	Chemotherapy	bEnd.3 cells; MPTP‑induced PD Mice	Parkinson’s disease	Achieved efficient drug delivery to the brain.	Liu et al. (2022b)
Ultrasonication	Nanoparticles	PTX	Folic acid	Chemotherapy	HepG2/A549/A375 cells; mice bearing subcutaneous tumor xenograft	Epithelial malignancies	Improved biocompatibility, prolonged circulation time, decreased immune responses and undesirable side effects.	Song et al. (2022)
Mechanical extrusion	Gold nanoparticles	PTX	Anti-EpCAM antibodies	PDT/Chemotherapy	4T1/RAW264.7 cells	Cancer	Selective cancer cell targeting.	Zhu et al. (2018)
Mechanical extrusion	PEG-b-PDLLA nanoparticles	PTX dimer/5,10,15,20-tetraphenylchlorine	–	PDT/Chemotherapy	HeLa cells; HeLa tumor-bearing nude mice	Cancer	Prolonged blood circulation; enhanced tumor accumulation; improved therapeutic outcomes with no obvious systemic toxicity.	Pei et al. (2018)
Ultrasonication	Bovine serum albumin nanoparticles	Gambogic acid/ indocyanine green	–	PDT/Chemotherapy	HeLa cells; HeLa tumor-bearing nude mice	Cancer	High drug loading capacity; evasion of immune clearance.	Wang et al. (2020c)
Ultrasonication/Mechanical extrusion	Copper(II)-coordinated nanodrug	Celastrol/ indocyanine green	–	PDT/Chemotherapy	U14 cells; U14 tumor-bearing nude mice	Cancer	Efficiently deplete the GSH and damage the ROS-scavenging system.	Zhu et al. (2023)
Mechanical extrusion	Lipid multichambered nanoparticles	PTX/IR780	Hyaluronic acid	PDT/Chemotherapy	A549/RAW264.7 cells; tumor-bearing nude mice	Lung cancer	Prolonged circulation in the blood; enhanced drug accumulation.	Zhang et al. (2021c)
Mechanical extrusion	PLGA nanoparticles	Cur dimer/pyro pheophorbide-α	–	PDT/Chemotherapy	SKOV3/normal epithelial/A549 cells	Cancer	High drug loading; selective drug release; combination of chemo- and photodynamic therapeutic effects.	Liu et al. (2022c)
Ultrasonication	Porous PLGA nanoparticles	Cur/dopamine	–	PDT/Chemotherapy	H22/RAW264.7/L929 cells; murine tumor model	Cancer	Prolonged blood circulation; superior photothermal effect.	Wang et al. (2020b)

3.1.1. Polymer-modified RBCM-coated nanoparticles

The hydrophobic nature of nanocarriers usually hinders intravenous drug administration, shortening drug half-life in the body and preventing sufficient accumulation at the lesion. Surface modification has emerged as an effective strategy to extend the lifetime of hydrophobic nanocarriers in circulation and prevent immune clearance. For example, hydrophilic PEGylated nanoparticles can evade immune clearance and prevent drug capture by the reticuloendothelial system (RES), prolonging drug circulation in the body (Li and Huang, 2010). However, this strategy is effective only after the first injection, and repeated injection may generate anti-PEG antibodies, which rapidly eliminate nanoparticles from the circulatory system (Wu et al., 2017a). In contrast, coating of polymer-modified nanodelivery systems with RBCMs stabilizes drugs and increases their bioavailability, thereby strengthening their therapeutic efficacy (Guo et al., 2021; Zhou et al., 2021; Safarpour et al., 2022; Zheng et al. 2023). In a recent study, PTX-loaded polymer nanocrystals coated with RBCMs escaped RES uptake and immunorecognition (Figure 3) (Zhai et al., 2020). Modification of nanocarriers with poly(lactic-co-glycolic acid) (PLGA), polylactic acid, poly(ε-caprolactone)–poly(ethylene glycol) (PCL-PEG) or polycaprolactone increased the anticancer activity of drugs through the enhanced permeability and retention effect (Xie et al., 2019; Wang et al., 2021b; Zhang et al., 2022).

Figure 3. Illustration of red cell membrane-biomimetic nanoparticles for escaping RES uptake and immunorecognition. (A) The components of PNM. (B) In vivo distributions of the PNM system. (C) In vivo and (D) ex vivo NIR fluorescence imaging of DiR-labeled PDN and PDNM (Zhai et al., 2020). © 2020. The Author(s). Reproduced with permission.

3.1.2. Targeted modification of RBCM-coated nanoparticles

Active targeting can lead to better drug bioavailability and fewer off-target side effects in vivo than passive targeting mediated by the enhanced permeability and retention effect. However, RBCMs lack specific proteins and molecules that could support active targeting. Therefore, the RBCM surface has been modified with the tumor-penetrating bispecific recombinant protein anti-EGFR-iRGD (Chen et al., 2018a; Zhang et al., 2018b), which can bind to integrins overexpressed in tumor blood vessels and cells as well as to the epidermal growth factor receptor overexpressed by most malignant tumors (Sha et al., 2015a, 2015b; Bian et al., 2016). In those studies, the membrane modification was achieved through physical lipid insertion instead of chemical conjugation in order to preserve the immune-evading biological components of RBCMs (Chen et al., 2018a; Zhang et al., 2018b).

In another study, functionalized RBCM-coated nanoparticles loaded with Cur were modified with DSPE-PEG3400-T807 (T807), allowing the particles to cross the blood-brain barrier (BBB) and target tau aggregates within neurons(Gao et al., 2020a). Cur is a natural anti-oxidant that can relieve the symptoms of Alzheimer’s disease (Chen et al., 2018b), and T807 binds strongly to hyperphosphorylated tau, inhibiting multiple pathways in Alzheimer’s pathogenesis (Do Carmo et al., 2021; Katharina Buerger et al., 2003). The surface of RBCMs has also been co-modified with triphenylphosphine cation (TPP) and T807 or rabies virus glycoprotein 29 (RVG29), resulting in nanodelivery systems that can cross the BBB and target mitochondria in neurons (Gao et al., 2020c; Han et al., 2020b; Liu et al., 2022b).

Nanoparticles have been modified by self-assembling hydrophobic stearic acid and hydrophilic carboxymethylcellulose, leading to selective drug release specifically in the acidic tumor microenvironment. In this approach, folic acid and PEG were conjugated to the RBCM surface via lipid chains in order to prolong drug circulation and improve targeting (Song et al., 2022).

3.1.3. Comprehensive therapy using RBCM-coated nanoparticles

PDT is a rapidly developing cancer treatment because it offers noninvasive therapy at a specific location in the body at a particular time (Felsher, 2003). In recent years, various photothermal materials have been used to develop bionic nanodelivery systems encapsulating natural products, including gold nanoparticles (AuNPs) (Zhu et al., 2018), 5,10,15,20-tetraphenylchlorin (Pei et al., 2018), indocyanine green (Wang et al., 2020c; Zhu et al., 2023), near-infrared dye IR780 (Zhang et al., 2021c), and pyropheophorbide-α (Liu et al., 2022c). For example, dopamine was allowed to self-polymerize in a weakly alkaline and aerobic environment such that it formed a polydopamine (PDA) layer on the surface of Cur-loaded nanoparticles, which were then coated with RBCMs. Cur and PDA acted as both chemotherapeutic and photothermal agents, and the combination of this nanosystem with near-infrared laser irradiation effectively promoted H22 cancer cell apoptosis and significantly reduced H22 tumor volume in mice (Figure 4) (Wang et al., 2020b).

Figure 4. Illustration of red cell membrane-biomimetic nanoparticles for combining chemotherapeutic and hyperthermia to enhancing antitumor effect. (A) The preparation of RBCM-cur@pPLGA/PDA nanoparticles and in vivo chemo-photothermal therapy. (B) In vivo antitumor efficacy of the various formulations in the H22 tumor model. (a) Tumor growth curves during the drug administration period. (b) Typical photographs of tumors isolated at the end of the administration. (c) Mean weights of the tumors isolated at the end of the administration. (d) Body weight changes in drug administration period (Wang et al., 2020b). © 2020. The Author(s). All rights reserved. Reproduced with permission.

3.2. WBC membranes

WBCs are an important part of the body’s defense system against inflammatory diseases, cancer, viral infections, and other disorders. Macrophages derived from monocyte differentiation, lymphocytes, neutrophils, and natural killer cells are all WBCs commonly used in bionic nano-drug delivery systems, which can be recruited to the tumor microenvironment during the development of malignant tumors (Han et al., 2018; Xinyue et al., 2018; Wang et al., 2021a). Therefore, WBC membranes have been used extensively to prepare bionic nanodelivery systems that can extend drug circulation in vivo and enhance active drug targeting, most recently of compounds with anti-inflammatory, anti-tumor or other effects (Table 3).

Table 3. Examples of drug-loaded nanoparticles coated with white blood cell membranes for disease treatment.

Membrane type	Preparation method	Nanosystem	Cargo	Combined therapy	Treatment model	Disease	Advantages	Ref.
Macrophages	Ultrasonication	–	Cur	Chemotherapy	Sprague-Dawley rats; primary neurons	Parkinson’s disease	Rapid and economic approach for the assembly of hydrophobic drugs into bioactive cellular nanovesicles.	Shen et al. (2021)
	Mechanical extrusion	Nanoparticles	Cur/Platycodon grandiflorum polysaccharide	Chemotherapy	RAW264.7 cells; human umbilical vein endothelial cells; ALI mouse models	Pneumonia	Effective accumulation in damaged lungs; inhibition of disease progression.	Li et al. (2022b)
	Mechanical extrusion	Albumin nanoparticles	PTX	Chemotherapy	B16F10 cells	Melanoma	Prolonged circulation without premature drug release; strong tumor targeting.	Cao et al. (2020)
	Ultrasonication/Mechanical extrusion	Liposomes	Cur/celecoxib	Chemotherapy	RAW264.7; aortic smooth muscle cells; aortic dissection model	Aortic dissection	Synergistic anti-inflammatory effect; optimal in vivo efficacy.	Liu et al. (2021)
	Mechanical extrusion	cskc-2-aminoethyldiisopr-opyl@Ma	PTX	Chemotherapy	Orthotopic breast cancer tumor model	Cancer	Favorable tumor-homing ability in systemic circulation; high biocompatibility; pH-responsive drug release.	Zhang et al. (2018a)
	Ultrasonication	Nanoparticles	PTX dimer Indoximod/chlorin e6	PDT/Chemotherapy	4T1 breast cancer cells; BALB/c nude mice	Cancer	Combined chemotherapy, PDT, and immunotherapy.	Liu et al. (2020a)
Neutrophils	Mechanical extrusion	PEG-PLGA nanoparticles	Celastrol	Chemotherapy	Orthotopic and ectopic pancreatic cancer models	Pancreatic cancer	Selective drug delivery; downregulation of pro-inflammatory factors.	Cao et al. (2019)
	Ultrasonication	PVP-TA nanoparticles	PTX	Chemotherapy	MDA-MB-231 cells; ectopic xenograft tumor-bearing mice	Breast cancer	Improved in vivo therapeutic effect and lowered systemic toxicity and good hemocompatibility.	Chowdhury et al. (2022)

3.2.1. Macrophage membranes

The WBCs most commonly used for bionic nanodelivery systems are macrophages derived from monocyte differentiation, lymphocytes, neutrophils, and natural killer cells (Parodi et al., 2013; Dash et al., 2020; Wang et al., 2022). Macrophage membranes contain several functional molecules such as CD45, CD11a and polysaccharides that help macrophage membrane-modified nanocarriers evade RES elimination, thereby prolonging drug circulation (Li et al., 2018). Other surface markers on the M1 macrophage membrane, such as CD80 and CD86, exert immune effects by activating T lymphocytes and helping the drug carrier target certain cells, while α4 integrin interacts with the vascular cell adhesion molecule-1 (VCAM-1) in cancer cells and binds to metastatic cancer cells, providing a new direction for tumor immunotherapy (Cao et al., 2016; Najafi et al., 2019). Nanoparticles encapsulated with M1 macrophage membranes were able to take advantage of M1 macrophages’ tendency to gravitate toward sites of inflammation and target tumors to increase the effectiveness of the drug therapy, compared to previous studies in which researchers used non-polarised or M2 macrophage membrane (Hu et al., 2020; Li et al., 2021a).

1. Targeted modification using macrophage membrane-coated nanoparticles

In a recent study, macrophage membrane-coated Cur-loaded nanocarriers prepared through an ultrasonication method interacted with target cells through surface proteins and vector ligands, avoiding elimination and ensuring selective delivery to disease sites (Shen et al., 2021). Another study reported the preparation of a Cur-based bionic drug delivery platform coated with macrophage membrane for the treatment of pneumonia. Platycodon grandiflorum polysaccharide direct nanocarriers to the lungs and target the site of pneumonia with macrophage membranes for dual targeting. The developed nanosystem significantly reduced cytokine storm syndrome and effectively inhibited acute lung injury in a mouse model (Li et al., 2022b). Coating macrophage membranes onto nanocarriers modified with albumin and the fusion peptide TAT-NBD enhanced drug delivery selectively to lesions (Cao et al., 2020; Liu et al., 2021). Together, the albumin and cell membrane layers significantly enhanced the cytotoxicity and apoptosis of paclitaxel, thereby improving the therapeutic efficacy in a melanoma xenograft mouse model. The fusion peptide TAT-NBD enhances the cell membrane penetration of loaded curcumin liposomes to promote their accumulation and penetration, and effectively exerts the anti-inflammatory effects of the drug.

To further improve drug targeting and therapeutic efficacy, a macrophage membrane-coated nanoparticle (cskc-PPiP/PTX@Ma) was developed for tumor-targeted chemotherapy delivery. Amphiphilic bola-pattern polymers with selected side chains were first synthesized via dual-end PEGylation of poly(β-amino ester) for PTX loading. The polymer was then functionalized with a cationic 2-aminoethyldiisopropyl (PPiP) group to enable pH-responsive drug release in the tumor microenvironment. A synthetic D-form oligopeptide with the cskc sequence was also used as the targeting ligand on the nanoparticle surface to enhance uptake by cancer cells (Figure 5). Cskc-PPiP/PTX@Ma showed high penetration efficiency at pH 6.5 in vitro and strong antitumor activity in mice bearing orthotopic tumors (Zhang et al., 2018a).

Figure 5. Illustration of macrophage membrane-biomimetic nanoparticles for escaping and drug-release mechanism (Zhang et al., 2018a). © 2018. The Author(s). All rights reserved. Reproduced with permission.

2. Comprehensive therapy using macrophage membrane-coated nanoparticles

To further improve drug efficacy, several studies have investigated biomimetic nanomedicines that can change their shape or size in response to various stimuli (Liu et al., 2020a). For example, one study used macrophage membranes to camouflage laser-responsive, shape-changeable nanoparticles loaded with the photosensitizer chlorin e6, PTX, and indoximod (Liu et al., 2020a). The macrophage membrane promoted drug circulation and tumor targeting, while chlorin e6 converted laser light into reactive oxygen species (ROS) to trigger the transformation of spherical micelles into nanofibers for strong retention and enhanced cellular internalization in tumors, leading to long drug circulation and sustained drug release. ROS also directly killed tumor cells by PDT and stimulated the generation of PTX from the PTX dimer, which significantly inhibited tumor growth and induced immunogenic cell death (Figure 6). Indoximod, for its part, activated antitumor immune responses. These observations indicate that this nanoplatform can achieve multimodal therapy to inhibit the growth of orthotopic breast tumors and lung metastasis.

Figure 6. Illustration of the construction and the drug-action mechanism of macrophage membrane-biomimetic nanoparticles (Liu et al., 2020a). © 2020. The Author(s). All rights reserved. Reproduced with permission.

These results also illustrate how nanodelivery systems coated with macrophage membrane can effectively evade RES clearance and accumulate at inflammatory and tumor sites. However, the high plasticity of macrophages means that they may be in different activation states or phenotypes when their membranes are isolated, which should be carefully controlled if the membranes are to be used for coating drug delivery systems.

3.2.2. Neutrophil membranes

Neutrophils are the most abundant type of WBCs in humans and the body’s first line of defense against invading pathogens (Chu et al., 2018). Neutrophils are rapidly activated in response to inflammatory stimuli and pass through the vascular endothelium to leave the circulation and migrate to sites of inflammation or tumors (Chu et al., 2018; Liu et al., 2022a; Tang et al., 2023). After activation by inflammatory responses, neutrophils bind to circulating tumor cells, preventing them from giving rise to distant metastatic tumors (Mantovani et al., 2008; Nguyen et al., 2009). Hence, neutrophils have been extensively studied as carriers for anti-inflammatory or antitumor drugs (Kang et al., 2017; Oroojalian et al., 2021). For instance, celastrol-loaded PEG methyl ether-block-PLGA nanoparticles were coated with neutrophil membrane to target pancreatic adenocarcinoma (Cao et al., 2019). The neutrophil membrane endowed nanoparticles with high affinity for tumor cells, reflecting the ability of neutrophils to accumulate at inflamed sites. In addition, the obtained nanoplatform penetrated the blood-pancreas barrier in mice bearing Panc02 tumors, achieving pancreas-targeted drug delivery and reducing systemic drug toxicity (Cao et al., 2019). In another study, the superior antitumor activity of the neutrophil membrane-cloaked NP construct was verified in an ectopic xenograft tumor (Chowdhury et al., 2022).

These results suggest that neutrophil membrane coating can significantly improve anticancer efficacy. However, neutrophils have a half-life of only 7 h and cannot be cultured in vitro, which greatly limits their application as drug delivery carriers.

3.3. Platelet membranes

Platelets, also known as thrombocytes, are the smallest non-nucleated blood myeloid cells derived from mature megakaryocytes of the bone marrow (Patel et al., 2005; Holinstat, 2017). Platelets are normally oval or disk-shaped, but their shape can vary substantially as a result of movement and deformation (Berger, 1970). Platelets form clots at the sites of blood vessel injury or blood leakage, and they collaborate with endothelial cells to release pro-inflammatory cytokines. In addition, they promote tumor metastasis by helping tumor cells escape from the immune system (Lefrançais et al., 2017; Li et al., 2018; Wang et al., 2020d; Kunde and Wairkar, 2021).

The platelet surface contains several immunoregulatory proteins, such as CD47 and CD55, as well as transmembrane proteins such as P-selectin. CD47 interacts with signals expressed by macrophages to favor immune escape, while P-selectin binds specifically to CD44 receptors upregulated on the surface of cancer cells to target tumor sites (Hu et al., 2015a, 2015b). Given that platelet membranes can be easily extracted and purified, they have been widely used as a coating to enable nanocarriers to adhere selectively to damaged vessels and pathogens (Table 4).

Table 4. Examples of drug-loaded nanoparticles coated with platelet membrane for disease treatment.

Preparation method	Nanosystem	Cargo	Combined therapy	Treatment model	Disease	Advantages	Ref.
Mechanical extrusion	Nanocrystals	PTX	Chemotherapy	4T1 cancer cells; operated BALB/c mice	Malignant tumor	Selective drug delivery; specific targeting of the coagulation cascade.	Mei et al. (2020)
Mechanical extrusion	Mesoporous calcium carbonate nanoparticles	Cur	Chemotherapy	MCF-7 cells; MCF-7 tumor-bearing BALB/c nude mice	Cancer	Ion signal switching from ‘regulating’ to ‘destroying’ cell function due to ion interference.	Zhang et al. (2021a)
Ultrasonication/Mechanical extrusion	chitosan-modified liposome	Cur	Chemotherapy	HepG2 cells; tumor bearing nude mice	Liver cancer	Significantly enhance the anticancer efficacy and minimal side effects.	Wan et al. (2023)
Mechanical extrusion	PLGA nanoparticles	Cur/ resveratrol	Chemotherapy	HBE/HUVEC cells; LPS-induced C57BL/6J mouse sepsis model	Acute lung injury	Targeted and accumulated into the inflammatory lungs.	Jin et al. (2022)
Ultrasonication	Janus aminated mesoporous silica nanomotors	PTX	PDT/Chemotherapy	Rabbit model of carotid artery damage	Atherosclerosis	Reduced vascular proliferation area.	Huang et al. (2020b)

3.3.1. Conventional platelet membrane-coated nanoparticles

Adjuvant chemotherapy is commonly used after surgery to prevent cancer recurrence and metastasis. However, the poor targeting capability and dose toxicity of adjuvant chemotherapeutics greatly limit their efficacy (Mei et al., 2020). One study explored the construction of a biomimetic platelet membrane-coated nanocrystal system, which combines tumor targeting by platelets with the high drug loading of nanocrystals. The resulting PTX-loaded biomimetic nanocrystals delivered large amounts of PTX selectively to tumor sites and improved mouse survival by targeting the coagulation cascade of nanoparticles (Mei et al., 2020). In another study, a biomimetic Cur-loaded Ca²⁺ nanogenerator was developed based on an ion interference strategy for tumor-specific therapy (Zhang et al., 2021a). The platelet membrane coating improved tumor-targeting ability, and Ca²⁺ and Cur were simultaneously released in the acidic tumor microenvironment. Cur promoted the release of Ca²⁺ from endoplasmic reticulum and inhibited Ca²⁺ efflux to increase Ca²⁺ overload and activate mitochondrial apoptotic signaling, suggesting the potential for synergistic cancer treatment based on Ca²⁺ overload therapy and chemotherapy.

3.3.2. Polymer-modified nanoparticles coated with platelet membranes

A study used chitosan-modified liposomes loaded with Cur, based on the idea of pH-responsive drug release by swelling and protonation. Through platelet membrane concealment, drugs showed better bioavailability and higher retention in the bloodstream. The integration of chitosan allowed Cur, upon accumulation in tumors via the EPR effect, to react to the intracellular pH of cancer cells and promote the effective release of cytotoxic medicines, which displayed great anticancer efficacy (Wan et al., 2023). Cur and resveratrol, two active ingredients in natural products, were encapsulated in PLGA nanoparticles and surface-coated with platelet membrane. Due to the intrinsic affinity of the platelet membrane for the site of inflammation, more medicines can be directed at the injured lung vasculature and successfully inhibit the pulmonary vascular injury model (Jin et al., 2022).

3.3.3. Comprehensive therapy using platelet membrane-coated nanoparticles

Atherosclerosis is a cardiovascular disease involving thickening of arterial walls, narrowing of the lumen, chronic inflammatory autoimmune responses, and abnormal lipid metabolism (Kattoor et al., 2017; Wu et al., 2017b; Wolf and Ley, 2019; Saigusa et al., 2020). In one treatment approach, the anti-proliferative drug PTX was combined with PDT to inhibit inflammatory macrophages in order to mitigate atherosclerosis (Huang et al., 2020b). Specifically, a drug-coated ‘balloon’ was developed using Janus aminated mesoporous silica (JAMS) nanomotors that offered high drug loading and sustained drug release. The nanomotor was co-loaded with PTX and anti-VCAM-1 antibody, then coated with platelet membrane to reduce drug leakage. Near-infrared irradiation promoted the penetration of drug-loaded JAMS into atherosclerotic plaques, where the nanoparticles were retained in part through interaction between the anti-VCAM-1 antibody and VCAM-1 overexpressed at plaque sites.

3.4. Cancer cell membranes

Cancer cells can be easily cultured in vitro, where they can rapidly multiply to provide abundant membranes that can be exploited to endow biomimetic nanodelivery systems with immune-evasive and host-like properties (Rao et al., 2016; Li et al., 2022c). Membrane proteins on the isolated cancer cell membranes, such as tissue factor-antigen, galectin-3 and E-cadherin can recognize other cancer cells to drive targeted drug delivery (Table 5) (He et al., 2020; Janiszewska et al., 2020). In addition, the transmembrane protein CD47 on cancer cell membranes can bind to SIRP-α on macrophages and trick the immune cells into thinking that the cancer cell-coated nanoparticle is endogenous and should not be phagocytosed (Fan et al., 2021).

Table 5. Examples of drug-loaded nanoparticles coated with cancer cell membranes for disease treatment.

Preparation method	Nanosystem	Cargo	Membrane modification	Combined therapy	Treatment model	Disease	Advantages	Ref.
Ultrasonication	Nanosuspensions	PTX	DWSW peptide	Chemotherapy	C6 cells; glioma-bearing mice	Glioma	Tumor growth inhibition; prolonged survival of glioma-bearing mice.	Fan et al. (2021)
Mechanical extrusion	Polylactic acid nanoparticles	PTX	–	Chemotherapy	4T1 cells; orthotopic 4T1 tumor-bearing mice	Breast cancer	Effective accumulation in tumor tissues; tumor growth inhibition; satisfactory biosafety in vivo	Han et al. (2020a)
Mechanical extrusion	PLGA nanoparticles	Cur		Chemotherapy	TC-1 tumor cells; TC-1 tumor model	Cancer	Elicited a dramatical antitumor immunity.	Liu et al. (2023a)
Mechanical extrusion	PLGA nanoparticles	PTX/siRNA-E7	–	Chemotherapy	HeLa cells; mice bearing subcutaneous HeLa xenograft	Cervical cancer	Specific, targeted drug delivery; reduced PTX-induced resistance; enhanced tumor suppression.	Xu et al. (2020)
Mechanical extrusion	siRNA modified polymer nanoparticles	PTX	–	Chemotherapy	U87MG cells; glioblastoma orthotopic xenografts models	Glioblastoma	Superior glioblastoma inhibition in vitro; prolonged survival in vivo; increased tumor accumulation by self-recognition and tumor-selective ‘homing’ to the homologous tumor.	Wang et al. (2023b)
Ultrasonication/Mechanical extrusion	PLGA nanoparticles	Cur/d-oxorubicin	PEG	Chemotherapy	TE10/doxorubicin cells; TE10 tumor-bearing mice	Multi-drug resistance in esophageal carcinoma	Excellent targeting and therapeutic effects; high biocompatibility; reduced side effects of chemotherapeutic drugs.	Gao et al. (2021)
Ultrasonication	Nanocrystals	PTX	Folic acid	Chemotherapy	SMMC-7721 cells; SMMC-7721 xenograft mouse model	Liver cancer	Increased cellular uptake; promotes cell apoptosis; enhanced targeting; improved bioavailability and accumulation in tumor tissues.	Shen et al. (2022)
Mechanical extrusion	Mesoporous silica nanoparticles	PTX	–	Magnetic hyperthermia/ chemotherapy	MDA-MB-231 cells	Breast cancer	Inhibition of tumor cell growth.	Cai et al. (2019)
Mechanical extrusion	PLGA nanoparticles	Cur/chlorine e6	–	PDT/chemotherapy	MCF-7 cells; tumor-bearing mice	Breast cancer	Inhibition of MCF-7 cell proliferation; superior tumor-targeted therapeutic effects.	Zhang et al. (2021b)
Mechanical extrusion	MnO2 nanoparticles	Cur	–	Sonodynamic therapy/chemotherapy	HepG2 cells; HepG2 tumor-bearing murine model	Breast cancer	Immune clearance evasion; enhanced tumor specificity; sonodynamic properties.	Yang et al. (2021)

3.4.1. Polymer-modified nanoparticles coated with cancer cell membranes

Nanoparticles coated with cancer cell membranes extracted from patient cancer cells are commonly used for the research of targeted cancer treatment. In order to prolong circulation of polymer-modified nanoparticles, they have been coated with membranes from 4T1 or C6 cancer cells (Han et al., 2020a; Fan et al., 2021). The resulting bionic nanocarriers avoided phagocytosis by macrophages and promoted drug accumulation in tumors, thereby reducing adverse reactions and enhancing therapeutic efficacy. The modification of the polymer also protects the loaded substance from enzymatic degradation and creates antigen and adjuvant deposition for controlled release (Liu et al., 2023a). In another study, PLGA nanoparticles co-loaded with PTX and small interfering RNA were camouflaged with HeLa cell membranes to achieve drug colocalization and synergistic antitumor effects (Xu et al., 2020). Similarly, negative charged small interfering RNA was condensed on the outer drug-loaded nanoparticles by electrostatic interaction and further protected by the cancer cell membranes also showed an excellent synergistic chemotherapy ability (Wang et al., 2023b). Modifying cancer cell membranes with PEG can further prolong drug circulation in the blood and reduce nonspecific binding between nanoparticles and serum proteins, thereby reducing systemic toxicity (Gao et al., 2021).

3.4.2. Targeted modification of cancer cell membrane-coated nanoparticles

Recent studies have focused on the modification of cancer cell membrane surfaces to enhance the targeting capability of coated nanoparticles. For example, SMMC-7721 cell membranes were modified with folic acid and used to coat PTX-loaded nanocrystals. The functionalized nanoplatform released PTX in a sustained manner and showed better targeting effects and biocompatibility than unmodified nanocrystals (Shen et al., 2022). In another study, the LWSW quorum sensing peptide was used to prepare a nanoplatform that selectively crossed the BBB and targeted glioma and neovascular endothelial cells (Ran et al., 2017). However, the nanoplatform was easily degraded by proteases in vivo, so the LWSW peptide was replaced by the DWSW peptide, which was more stable in serum and therefore preserved glioma targeting. In fact, adding DWSW to the C6 glioma membrane coating stabilized the drug delivery system in the brain of glioma-bearing mice (Fan et al., 2021).

3.4.3. Comprehensive therapy using cancer cell membrane-coated nanoparticles

Breast cancer poses a serious threat to women worldwide, as current treatments cannot achieve complete recovery (Hare et al., 2017; Wilkinson & Gathani, 2022). In one study, MDA-MB-231 cell membrane-coated mesoporous silica nanoparticles were co-loaded with superparamagnetic ferroferric oxide and PTX to combine chemotherapy and magnetic hyperthermia against breast cancer. When mesoporous silica particles were exposed to an alternating magnetic field, they oscillated to convert magnetic field energy to heat energy. High temperatures interfered with the biological regulatory processes in tumor cells, such as proliferation and metabolism, inducing cell necrosis or apoptosis, while the MDA-MB-231 cell membrane coating helped nanoparticles avoid immune rejection (Cai et al., 2019). In a similar study, PLGA nanoparticles co-loaded with Cur and chlorin e6 were encapsulated in MCF-7 cell membranes, which significantly increased their uptake by MCF-7 cells, while ROS generated by chlorin e6 under near-infrared light killed tumor cells (Zhang et al., 2021b).

To improve the therapeutic efficacy of PDT, Cur-loaded MnO₂ nanoparticles were coated with cancer cell membrane. The resulting nanosystem evaded immune clearance and supported Cur-based sonodynamic therapy in parallel with the compound’s ability to stimulate apoptosis and inhibit proliferation (Yang et al., 2021). In addition, the MnO₂ nanoparticles acted as catalase to alleviate hypoxia in the acidic tumor microenvironment.

These results indicate that coating nanodelivery systems with cancer cell membranes can help them evade immune clearance and target tumors, which cause increased the long circulation, self-binding capacity, and recognition functionalities of the cancer cells, thereby improving drug biodistribution and enhancing antitumor effects. Nevertheless, the use of patient-derived tumor cells to develop nanocarriers for specific antitumor drugs requires further investigation.

3.5. Hybrid membranes

Hybrid membrane-coated biomimetic nanocarriers are prepared by fuzing two different cell membranes and combining the functions and biomarker activities of both cell types (Table 6) (Berta Esteban-Fernández et al., 2018; Raza et al., 2021; Li et al., 2022d). In a recent study, murine J774A.1 cells and head and neck tumor HN12 cells were used to design a composite cell membrane-camouflaged biomimetic nanoplatform (He et al., 2018). Coating the nanoparticles with the hybrid membrane favored their selective internalization by tumor cells, while their uptake by WBCs was significantly reduced, improving the toxic effects of drugs on cancer cells. In vivo studies in a mouse xenograft model of head and neck cancer also showed that hybrid membrane prolonged the circulation of nanoparticles and significantly enhanced their ability to target tumors (Figure 7) (He et al., 2018). In another studies, formulated a hybrid biomimetic camouflage delivery system by fuzing breast cancer cell membranes and activated fibroblast membranes possess outstanding dual-targeting ability, which addressing the microenvironment of breast cancer immunosuppression (Zang et al., 2022; Wang et al., 2023a).

Figure 7. Illustration of the schematic presentation of composite leukocyte and tumor cell membrane-camouflaged liposome and potential application in cancer treatment and diagnosis (He et al., 2018). © 2018. The Author(s). All rights reserved. Reproduced with permission.

Table 6. Examples of drug-loaded nanoparticles coated with hybrid membranes for disease treatment.

Membrane type	Preparation method	Nanosystem	Cargo	Combined therapy	Treatment model	Disease	Advantages	Ref.
White blood cells/cancer cells	Mechanical extrusion	Liposomal nanoparticles	PTX	Chemotherapy	HN12 cells; xenograft mouse models	Cancer	Prolonged blood circulation; enhanced tumor accumulation; decreased systemic toxicity.	He et al. (2018)
White blood cells/cancer cells	Ultrasonication/Mechanical extrusion	PLGA nanoparticles	PTX	Chemotherapy	143B cells; xenograft tumor models	Osteosarcoma	Promoted drug uptake; induction of osteosarcoma cell apoptosis; superior targeting efficacy; decreased toxicity.	Cai et al. (2022)
Platelets/cancer cells	Ultrasonication	Lyotropic liquid crystalline lipid nanoparticles	Triptolide/sorafenib	Chemotherapy	Huh-7 cells; tumor-bearing mice	Hepatocellular carcinoma	Long circulation; high tumor targeting ability; promoted tumor cell apoptosis; improved synergistic and attenuation effects.	Li et al. (2021b)
Cancer cell/fibroblast	Mechanical extrusion	solid lipid nanoparticles	PTX/ glycolysis inhibitor PFK15	Chemotherapy	4T1/NIH3T3 cells; primary tumor model	Breast cancer	Effectively targeted the metabolic network between cancer cells and CAFs by dual-targeting ability.	Zang et al. (2022)
Cancer cell/fibroblast	Mechanical extrusion	MnO2 nanoparticles	Cur/mPDA	PDT/Chemotherapy	4T1/NIH3T3 cells; primary tumor model	The triple-negative breast cancers	Conducive to the penetration and targeting of drugs to tumor cells in the deep tissues.	Wang et al. (2023a)
Red blood cells/platelets	Ultrasonication/Mechanical extrusion	Gold nanoparticles	Cur	PDT/Chemotherapy	B16-BL6 cells	Melanoma	Controlled drug release; high tumor targeting ability; immune escape; enhanced therapeutic effects in vitro.	Kim et al. (2020)

The tumor microenvironment of osteosarcoma comprises various types of stromal cells, which secrete inflammatory cytokines and other humoral factors to establish an inflammatory environment (Lei et al., 2020; Yu et al., 2020). Hence, a hybrid membrane prepared from macrophages and 143B osteosarcoma cells was previously used to coat PLGA nanoparticles for targeted osteosarcoma chemotherapy (Cai et al., 2022). Similarly, the long functional life of platelet membranes was combined with the homologous targeting ability of human liver cancer Huh-7 cell membrane to treat hepatocellular carcinoma. The hybrid membrane was used to coat lyotropic liquid crystalline lipid nanoparticles co-loaded with sorafenib and triptolide (Li et al., 2021b). A similar strategy was used to coat Cur-loaded gold nanoparticles with hybrid RBC/platelet membrane, allowing the particles to evade phagocytosis, induce weaker immune responses, and support PDT (Kim et al., 2020).

Overall, hybrid cell membranes, by combining characteristics from two cell types, provide a potentially more flexible approach to targeted cancer treatment than single membrane-coated nanodelivery systems. However, several challenges remain to be addressed in the functionalization of nanodelivery systems with multiple cell membranes. For example, how to determine the incorporation ratio of the two cell membranes and ensure successful hybridization of the two cell membranes without damaging the cell membrane surface proteins.

4. Conclusions

Natural products have unique values and advantages in disease treatment and health care. The present manuscript has reviewed the recent scientific literature covering the last five years, in the attempt to evaluate the development of a cell-based biomimetic technology related to the delivery of natural products. Some compounds such as PTX, Cur, gambogic acid, resveratrol, triptolide and celastrol, possess myriads of pharmacological activities in vitro, although their bioavailability is virtually nil (Huang et al., 2023a). Cell membrane-based biomimetic nanosystems have emerged to solve this problem. First, these formulation nanodelivery strategies, such as liposomes, solid lipid nanoparticles, nanoemulsions, micelles and polymer nanoparticles, which can dramatically improve the efficacy of the natural active compounds by increasing of the bioavailability of these substances. Modification with PLGA, polylactic acid, PCL-PEG, polycaprolactone and other polymer could enhance permeability and retention effect of nanocarriers. With respect to cell membrane-based biomimetic technology, the central idea is to attach cell membrane to nanosystems superficially, before directing them inside the human body. Due to the preserved membrane compositions and antigens, some unique features and functions are inherited in these biomimetic systems, including specific neutralization of pathological molecules, immune escape capability, prolonged blood circulation, and homing to disease lesions. Additionally, further modifying folic acid, antibodies, proteins, fatty acids, and other substances by inserting lipids on the cell membrane’s surface can not only improve the bionic agent’s active targeting capability but also give it the ability to respond to stimuli. Hence, by employing cell-based biomimetic nanosystems, the drug solubility and stability can be significantly upregulated. Unwanted and adverse effects related to drug payload, particularly strong off-target toxicity, in addition to improve short half-life and low bioavailability, were prohibited.

Despite cell membrane-camouflaged nanoparticles are quite prospective in delivering natural products (Table 7), they are still in their infancy stage and many challenges need to be overcome for successful translation into the clinic. There is no clinically applicable way to guarantee the controllability, efficacy, and safety of cell membrane biomimetic nanodelivery system preparation. For instance, membrane extraction is currently performed through repeated freeze-thawing, ultrasonication or grinding-up in order to minimize the use of organic reagents or strong acids or bases, which could inactivate membrane proteins. Nevertheless, the loss of some membrane proteins during extraction is inevitable. In addition, the methods used for the fusion of cell membranes and nanodelivery systems are inefficient and can lead to substantial batch-to-batch variation, making scale-up difficult. Sodium dodecyl sulfate–polyacrylamide gel electrophoresis and western blotting can confirm the presence, but not function, of the appropriate surface components of the source cell membranes in biomimetic preparations. Therefore, additional research is required to develop more effective extraction and preparation methods to promote the application of natural products in the emerging era of nanoparticle-driven personalized medicine. The current studies have demonstrated that only application of PTX and Cur were extensively recovered, while other active components such as gambogic acid and resveratrol were not well researched. In addition, the current combined therapy of natural products nanosystems mainly focuses on magnetic hyperthermia, PDT and sonodynamic therapy. In the future studies, more emphasis can be placed on com­bining with other combination therapy strategies, such as radiation therapy and immunotherapy. Since these years are living an increasing interest toward natural products. Whereas, the current research on natural products nanosystems mainly focuses on monomer drugs, and there are relatively few studies on the effects of two or more drugs co-contained in the nanosystems. In future studies, more emphasis can be placed on compound drugs to achieve the reasonable collocation of different natural products to enhance the efficacy.

Table 7. Summary of cell membrane types and their characteristics.

Types		Material core	Preparation method	Advantages	Ref.
RBC membrane		Nanomicelles; nanostructured lipid carriers; nanocrystals; polymer/protein/Gold nanoparticles	Ultrasonication; mechanical extrusion	Escape the phagocytosis of immune cells and longer blood circulation.	Zhang et al. (2022)
WBC membrane	Macrophage membrane	Protein nanoparticles; liposomes		Evade RES elimination, prolonging drug circulation and exert immune effects.	Li et al. (2018)
	Neutrophil membrane	Polymer nanoparticles		BBB penetrating, infarct core targeting, inflammation neutralization, and immune evasion.	Liu et al. (2022a); Tang et al. (2023)
Platelet membrane		Nanocrystals; calcium carbonate/ SiO2 nanoparticles		Protect nanoparticles from phagocytosis by macrophages, strong affinity for a variety of cancer cells and the site of inflammation.	Jin et al. (2022); Wan et al. (2023)
Cancer cell membrane		Nanosuspensions; polymer/SiO2/MnO2 nanoparticles; nanocrystals		Evade immune recognition and actively homologous targeting.	Li et al. (2022c)
Hybrid membrane		Liposomal/polymer/Gold nanoparticles		Inherit the functions of each membrane by fuzing cell membranes from various sources.	Li et al. (2022d); Zang et al. (2022)

Altogether, it can be expected that by developing the research of properties and additional embellishment of the different cell membranes, choosing the suitable drug delivery system and studding the surface of these formulations with cell membranes, the development of an efficient and safe drug delivery system could be achieved.

Authors’ contributions

Writing—original draft preparation, Yifeng Zhang and Qian Zhang; writing—review and editing, Chunhong Li. Ziyun Zhou and Hui Lei.; visualization and supervision, Minghua Liu and Dan Zhang. All authors agree to be accountable for all aspects of the work.

Abbreviations
PTX	=	paclitaxel
Cur	=	curcumin
PEG	=	polyethylene glycol
RBCs	=	red blood cells
WBCs	=	white blood cells
PDT	=	photodynamic therapy
CD47	=	integrin-associated protein
RBCMs, RBC	=	membranes
RES	=	reticuloendothelial system
PLGA	=	poly(lactic-co-glycolic acid)
PCL-PEG	=	poly(ε-caprolactone)–poly(ethylene glycol)
BBB	=	blood-brain barrier
AuNPs	=	gold nanoparticles
VCAM-1	=	vascular cell adhesion molecule-1
PPiP	=	cationic 2-aminoethyldiisopropyl
ROS	=	reactive oxygen species
JAMS	=	Janus aminated mesoporous silica
PDLLA	=	poly(D,L-lactic acid)
RVG29	=	rabies virus glycoprotein
TPP	=	triphenylphosphine cation
PNM	=	paclitaxel-nanoparticles-erythrocyte membrane
NIR	=	near infrared radiation
PDN	=	paclitaxel/DiR hybrid nanoparticles
PDNM	=	paclitaxel/DiR-nanoparticles-erythrocyte membrane
pPLGA	=	porous poly(lactic-co-glycolic acid)
PDA	=	polydopamine.

Disclosure statement

The authors report there are no competing interests to declare.

Additional information

Funding

This research was funded by Natural Science Foundation of Sichuan Province (number 2023NSFSC0666); Sichuan Science and Technology program (number 2022YSF0625); Joint Project from Luzhou City and Southwest Medical University (number 20ykdz0008); the key research and development project fund of social development of Luzhou Science and Technology Bureau (number 2022-SYF-56); basic Scientific Research Fund of Southwest Medical University (number 2021CXYY03) and the Student’s Platform for Innovation and Entrepreneurship Training Program (number 202010632072).