Biomembrane-Derived Nanoparticles in Alzheimer’s Disease Therapy: A Comprehensive Review of Synthetic Lipid Nanoparticles and Natural Cell-Derived Vesicles

Figures & data

Figure 1 Challenges of conventional AD drugs. (1) Drugs are often degraded during intrahuman circulation due to their poor stability or stimulation by factors within the body; (2) the special composition of the BBB sets up natural barriers for AD drug delivery, greatly reducing the penetration rate of drugs; and (3) drugs that cross the BBB into the brain are randomly distributed to the whole brain, lacking targeted therapeutic effects. Image created with Biorender.com.

Figure 2 Schematic snapshot of the blood–brain barrier. Reprinted from Xu L, Nirwane A, Yao Y. Basement membrane and blood-brain barrier. Stroke Vasc Neurol. 2019;4(2):78–82. Creative Commons.¹⁴

Table 1 Characters of Biomembrane-Derived Nanoparticles for AD Treatment

Type of Biomembrane Nanoparticles	Synthetic Liposomes	HDL Nanoparticles	Cell Membrane-Based Nanoparticles	Natural Extracellular Vesicles
Synthesis or isolation	Relatively easy-to-do and scalable	Easy-to-do and scalable	Easy-to-do in lab but with limited scalability	Most complex and with limited scalability
Engineering	Endure a wide range of physical (eg extrusion or sonication) and chemical modifications	Endure physical and chemical modifications well	Able to endure moderate physical and chemical modifications	Relatively sensitive to physical and chemical modifications
Biomimetic potential	Not suitable for complicated biological modification (eg embedment of multiple surface proteins)	HDL-based nanoparticles synthesized using apolipoproteins derived from HDL have more powerful functions than endogenous HDL	Inherit complex surface protein profile from source cells Inherently display functional biomolecules (eg immunomodulatory proteins and molecular recognition ligands) on the membrane surface	Harbor a wide range of bioactive molecules both on the membrane surface and encapsulated inside Additional biological characteristics (eg surface markers, signaling proteins, nucleic acids) could be introduced by parent cell-level engineering
Reproducibility and quality control	Fabrication process relatively reproducible and less challenging to develop standardized production and characterization procedures	Fabrication process relatively reproducible but HDL is limited to human sources; Standardized methods for manufacture and quality control have not been established	Batch-to-batch reproducibility could be limited by the condition of source cells Standardized methods for manufacture and quality control still to be established	Batch-to-batch reproducibility particularly sensitive to parental cell conditions and isolation methods
Biosafety and immunogenicity	Good biocompatibility; could be immunogenic due to synthetic components and coatings	Good biocompatibility; Low immunogenicity	Good biocompatibility; immunogenicity could be minimized when used autologously	Good biocompatibility; immunogenicity is highly tunable (from nonimmunogenic to specifically immunogenic against diseased cells) according to source and biological modification

Table 2 Summary of the Advantages and Disadvantages of Different Methods of Engineering Biomembranes

Methods of Engineering Biomembranes		Explanation	Advantages	Disadvantages
Physicochemical methods	Membrane hybridization	Membrane hybridization refers to hybridizing two different types of biological membranes or biological membranes and liposomes into a mixed membrane.	Obtain the individual characteristics of two different cell membranes simultaneously; Convenient and compatible with other cell membrane modification schemes; Avoid contaminating the membranes with unwanted chemicals	Susceptible to the hydrophobic properties of lipid molecules
	Postinsertion method	The postinsertion method is a nondestructive method for the physical insertion of functional ligands into biomembranes.	Avoid damaging the membrane structure; Simple and robust; Control the ligand quantity by adjusting the lipid-tethered ligand input	The instability of the inserted molecules might limit the effectiveness of the physical approach.
Chemical methods		With different covalent methods, moieties can be connected onto the membrane surface by coupling with functional groups on the membranes.	Convenient for modifying biological membranes with functional ligands while preserving their biological competence	Their harsh reaction conditions may destroy cell viability or membrane structure.
Biological engineering	Metabolic engineering	Metabolic engineering utilizes natural biosynthetic pathways to express ligands on biomembranes without destroying the membrane structure.	Avoid damaging the membrane structure; Flexible and versatile	May cause some uncontrolled toxicity or immunogenecity concerns of engineered cells
	Gene engineering	Gene engineering uses biological tools to selectively modulate cell genes to modify the needed proteins or antibodies on the cell membranes.	Enable the cells to express the needed proteins on their membrane surface easily

Figure 3 Schematic diagram and advantageous study of liposomes in AD-targeted therapy. (A) Schematic diagram of liposome-targeted therapy for AD through different pathways. Image created with Biorender.com. (B) Schematic illustration of the strategy for improving AD-related pathology by Tf-modified osthole liposomes. Reprinted with permission from Dove Medical Press. Kong L, Li XT, Ni YN, et al. Transferrin-modified osthole PEGylated liposomes travel the blood-brain barrier and mitigate Alzheimer’s disease-related pathology in APP/PS-1 mice. Int J Nanomedicine. 2020;15:2841–2858.²⁸ (C) Real-time imaging observation after intravenous administration of varying liposomal formulations in APP/PS-1 mice (n=3). Reprinted with permission from Dove Medical Press. Kong L, Li XT, Ni YN, et al. Transferrin-modified osthole PEGylated liposomes travel the blood-brain barrier and mitigate Alzheimer’s disease-related pathology in APP/PS-1 mice. Int J Nanomedicine. 2020;15:2841–2858.²⁸ (D–F) The biosafety of Tf-Pep63-Lip in vivo and in vitro: Tf-Pep63-Lip and Tf-Lip do not induce adverse effects in vivo and in vitro. Reprinted from Yang X, Li X, Liu L, et al. Transferrin-Pep63-liposomes accelerate the clearance of Abeta and rescue impaired synaptic plasticity in early Alzheimer’s disease models. Cell Death Discov. 2021;7(1):256. Creative Commons.²⁹

Figure 4 Schematic diagram and advantageous study of HDL-based nanoparticles delivering drugs in AD-targeted therapy. (A) Schematic diagram of HDL nanoparticles (exemplified by APLN/MB) delivering drugs through the BBB via receptor-mediated endocytosis with the help of LRP1 and other receptors to target AD. Reprinted from Han G, Bai K, Yang X, et al “Drug-Carrier” synergy therapy for amyloid-beta clearance and inhibition of tau phosphorylation via biomimetic lipid nanocomposite assembly. Adv Sci. 2022;9(14):e2106072. © 2022 The Authors. Advanced Science published by Wiley-VCH GmbH. Creative Commons.⁷⁶ (B) After α-M loading, apolipoprotein E (ApoE)-reconstituted high-density lipoprotein nanocarriers (ANCs) can inhibit the formation of Aβ oligomers and fibrils and hasten Aβ cellular degradation. Reprinted from Song Q, Song H, Xu J, et al. Biomimetic ApoE-reconstituted high density lipoprotein nanocarrier for blood-brain barrier penetration and amyloid beta-targeting drug delivery. Mol Pharm. 2016;13(11):3976–3987, Copyright © 2016 American Chemical Society.⁷⁵ (C) Brain distribution of ANC following intravenous administration. Reprinted from Song Q, Song H, Xu J, et al. Biomimetic ApoE-reconstituted high density lipoprotein nanocarrier for blood-brain barrier penetration and amyloid beta-targeting drug delivery. Mol Pharm. 2016;13(11):3976–3987, Copyright © 2016 American Chemical Society.⁷⁵ (D) ANC-α-M decreased amyloid deposition and attenuated microgliosis in the brains of SAMP8 mice. (**p < 0.01, ***p < 0.001, significantly different from that in SAMP8 mice treated with NS; ^#p < 0.05, ^###p < 0.001, significantly different from that in the SAMR1 mice treated with NS. Black arrows point to amyloid plaques and white arrows point to CD45-positive activated microglia.) Reprinted from Song Q, Song H, Xu J, et al. Biomimetic ApoE-reconstituted high density lipoprotein nanocarrier for blood-brain barrier penetration and amyloid beta-targeting drug delivery. Mol Pharm. 2016;13(11):3976–3987, Copyright © 2016 American Chemical Society.⁷⁵ (E) In vivo accumulation of ANC (red) surrounding Aβ aggregates (green) in the cortex and hippocampus following intravenous administration. Reprinted from Song Q, Song H, Xu J, et al. Biomimetic ApoE-reconstituted high density lipoprotein nanocarrier for blood-brain barrier penetration and amyloid beta-targeting drug delivery. Mol Pharm. 2016;13(11):3976–3987, Copyright © 2016 American Chemical Society.

Table 3 Summary of the Features Between Different Cell Membrane-Based Nanoparticles

Cell Membrane Type	Key Features	Targeting Ability	Stage of Development	Limitations
Red blood cell membrane	Long systemic circulation (0~ 120 d in human and 0~ 50 d in mice) Immune evasion Surface expresses CD47 protein	RES-targeting	Clinical trial	Surface modification may induce hemolysis
Platelet membrane	Long systemic circulation (0~ 7 to 10 d) Survey for damage Immune evasion Surface expresses CD47, CD55 and CD59 Self-aggregation Adhesion at tumor sites	Injury sites-targeting	Clinical trial	Small proportion of blood Undesirable activation
Leukocyte membrane	Amoeboid movement Close relationship with inflammation Immune evasion Endothelial adherence Solid and metastatic tumor interaction	Diseased sites-targeting	Lab study	The least component in blood Various subspecies with different morphology Limited to certain tumors
Cancer cell membrane	“Homologous adhesion” to tumor sites Drives tumor-specific immunity	Tumor-targeting	Lab study	Shorter circulation time
Stem cell membrane	Long circulation Tumor-specific properties	Tumor-targeting	Lab study	Low specificity
Fibroblast cell membrane	Homologous targeting ability	Cancer-associated fibroblasts-targeting	Lab study	Part targeting to normal fibroblast
Bacterial membrane	Stimulating innate immunity Promoting adaptive immunity	Homologous-targeting	Lab study	Need to remove peptidoglycan during extraction

Notes: Adapted from ref⁹⁸ with permission from Springer. Copyright 2018.

Figure 5 Schematic diagram and advantageous study of cell membrane-based nanoparticles delivering drugs in AD-targeted therapy. (A) Schematic diagram of cell membrane-based nanoparticles as drug carriers for targeted treatment of AD. Image created with Biorender.com. (B) Compared with the saline (control) group, no indicators of damage were observed for these organs after treatment. (C) The most intense distribution in the brain was displayed in the DIR-tagged RVG/TPP-MASLNs-treated mice and was further confirmed by the fluorescence intensity identified in the isolated brain homogenate. (*p < 0.05 compared with MASLNs.) (D) Administration of GS-loaded formulations slowed the alleviation of degenerative alterations of hippocampal neurons in AD mice to different extent. (Red arrows point to the damaged neurons.) Adapted with permission from KeAi Publishing. Han Y, Gao C, Wang H, et al. Macrophage membrane-coated nanocarriers Co-Modified by RVG29 and TPP improve brain neuronal mitochondria-targeting and therapeutic efficacy in Alzheimer’s disease mice. Bioact Mater. 2021;6(2):529–542.¹⁰⁰

Figure 6 Schematic diagram and advantageous study of extracellular vesicles delivering drugs in AD-targeted therapy. *(A) Schematic diagram of variously modified extracellular vesicles capable of crossing the BBB to target AD. Image created with Biorender.com. (B) Exo-Que enhanced the bioavailability, achieved brain targeting and improved cognitive and functional symptoms in OA-induced AD mice. (C) Exo-Que significantly enhanced accumulation of Que in brain and highly enhanced fluorescence of Que was observable in brain in Exo-Que-treated group. (*p < 0.05, **p < 0.01.) (D) Compared with OA and OA + Que group, Exo-Que significantly increased the number of NeuN-positive neuron cells in hippocampal CA1 region, CA3 region and DG region. (*p < 0.05, **p < 0.01.) (E) H&E staining results showed that the neuronal layers in the hippocampus showed integrity and orderliness maintaining intact neuronal cells structure with clear line and abundant cytoplasm in OA + Exo-Que group. Reprinted from Qi Y, Guo L, Jiang Y, Shi Y, Sui H, Zhao L. Brain delivery of quercetin-loaded exosomes improved cognitive function in AD mice by inhibiting phosphorylated tau-mediated neurofibrillary tangles. Drug Deliv. 2020;27(1):745–755. Creative Commons.

Xu L, Nirwane A, Yao Y. Basement membrane and blood-brain barrier. Stroke Vasc Neurol. 2019;4(2):78–82. doi:10.1136/svn-2018-000198

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Kong L, Li XT, Ni YN, et al. Transferrin-modified osthole PEGylated liposomes travel the blood-brain barrier and mitigate Alzheimer’s disease-related pathology in APP/PS-1 mice. Int J Nanomedicine. 2020;15:2841–2858. doi:10.2147/IJN.S239608

 PubMed Web of Science ®Google Scholar

Yang X, Li X, Liu L, et al. Transferrin-Pep63-liposomes accelerate the clearance of Abeta and rescue impaired synaptic plasticity in early Alzheimer’s disease models. Cell Death Discov. 2021;7(1):256. doi:10.1038/s41420-021-00639-1

 PubMed Web of Science ®Google Scholar

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 Web of Science ®Google Scholar

Song Q, Song H, Xu J, et al. Biomimetic ApoE-reconstituted high density lipoprotein nanocarrier for blood-brain barrier penetration and amyloid beta-targeting drug delivery. Mol Pharm. 2016;13(11):3976–3987. doi:10.1021/acs.molpharmaceut.6b00781

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Han Y, Gao C, Wang H, et al. Macrophage membrane-coated nanocarriers Co-Modified by RVG29 and TPP improve brain neuronal mitochondria-targeting and therapeutic efficacy in Alzheimer’s disease mice. Bioact Mater. 2021;6(2):529–542. doi:10.1016/j.bioactmat.2020.08.017

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