Recent Advances of Membrane-Cloaked Nanoplatforms for

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Recent advances of membrane-cloaked nanoplatforms for biomedical applications Bengang Xing, Xiangzhao Ai, Ming Hu, zhimin wang, Wenmin Zhang, Juan LI, Jun Lin, and Huang-Hao Yang Bioconjugate Chem., Just Accepted Manuscript • DOI: 10.1021/acs.bioconjchem.8b00103 • Publication Date (Web): 06 Mar 2018 Downloaded from http://pubs.acs.org on March 7, 2018

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Bioconjugate Chemistry

Recent advances of membrane-cloaked nanoplatforms for biomedical applications

Xiangzhao Ai,† Ming Hu,† Zhimin Wang,† Wenmin Zhang,†,‡ Juan Li,‡ Huanghao Yang,‡ Jun Lin,§ and Bengang Xing*,†,‡

†

Division of Chemistry and Biological Chemistry, School of Physical & Mathematical Sciences,

Nanyang Technological University, Singapore, 637371 ‡

College of Chemistry, Fuzhou University, Fuzhou, Fujian, 350116, China

§

State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied

Chemistry, Chinese Academy of Sciences, Changchun, 130022, China

Abstract In terms of the extremely small size and large specific surface area, nanomaterials often exhibit unusual physical and chemical properties, which have recently attracted considerable attention in bionanotechnology and nanomedicine. Currently, the extensive usage of nanotechnology in medicine holds the great potential for precise diagnosis and effective therapeutics of various human diseases in clinical practice in past decades. However, a detailed understanding regarding how nanomedicine interact with the intricate environment in complex living systems remains a pressing and challenging goal. Inspired by the diversified membrane structures and functions of natural prototypes, research activities on biomimetic and bioinspired membranes, especially for those cloaked with nano-sized platforms has increased exponentially. By taking advantages of the flexible synthesis and multiple functionality of nanomaterials, a variety of unique nanostructures including inorganic nanocrystals and organic polymers have been widely devised to substantially integrate with intrinsic bio-moieties such as lipids, glycans, even cell and bacteria membrane components,

which endowed these abiotic nanomaterials with

specific biological functionalities for the purpose of detailed investigation of the complicated interactions and activities of nanomedicine in living bodies, including their immune response activation, phagocytosis escape, and subsequent clearance from vascular system. In this review, we summarized the strategies established recently for the development of biomimetic membrane-cloaked nanoplatforms derived from inherent host cells (e.g., erythrocytes, leukocytes,

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platelets and exosomes) and invasive pathogens (e.g., bacteria and viruses), mainly attributed to their versatile membranes properties in biological fluids. Meanwhile, the promising biomedical applications based on these diverse moieties-inspired nanoplatforms, such as selective drug delivery in targeted sites and effective vaccines development for diseases prevention, have also been outlined. Finally, the potential challenges and future prospectives of the biomimetic membrane-cloaked nanoplatforms were also discussed.

Introduction Currently, the remarkable progresses of nanomedicine based on extensive usage of nanotechnologies have received considerable interests for their prospective potential in precise diagnosis and effective therapeutics of various diseases including cancer, cardiovascular diseases as well as neurological disorders,1-6 mostly owing to the unique physical and chemical properties of diverse nanomaterials in terms of the nanoscale size effect and high surface-to-volume ratio.7-12 Despite the continuous progresses in recent decades, a detailed understanding regarding how nanomedicine interact with the intricate environment in living systems, still remains a pressing and challenging goal.13-15 Many significant effects of designed structures in nanomedicine for their unique bio-activities and functions, especially for their dynamic transport pathways in vascular system, clearance, phagocytic immune-mediated degradation, as well as the potential binding sites of nanomedicine in living bodies, have not yet been thoroughly elucidated.16-18 To this end, the well-designed nanoplatforms are highly demanded as advanced biotechnological tools to fully understand the detailed behaviors of nanomedicine in complicated physiopathological processes including disease surveillance, sensitive diagnosis and targeted therapeutics.19-21 In fact, there are plenty of native prototypes (e.g., cells, virus, bacteria, etc) with their inherent properties to regulate diverse biological processes (e.g., growth, metabolism, immunity, etc), which serve as a major source to motivate us constructing biomimetic nanostructures for the investigations of nanomedicine bio-activities in vivo.22-24 Particularly, inspired by the diversified membrane structures and functions of these natural bio-moieties, research activities on biomimetic membranes, especially for those cloaked with nano-sized platforms, has increased exponentially in recent decades.25-28 So far, on the basis of the flexible synthesis and multiple functionality of nanomaterials, a variety of unique nanostructures including inorganic nanocrystals (e.g., gold


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nanoparticles (AuNPs), etc) and organic polymers (e.g., poly(lactic-co-glycolic acid) (PLGA) nanoparticles, etc) have been widely devised to substantially integrate with intrinsic bio-moieties such as lipids, glycans, even cell and bacteria surface components.29-31 These hybridized nanoplatforms endowed the abiotic nanomaterials with specific biological functionalities for the explorations of complicated interactions and activities of nanomedicine in living conditions, including immune response activation, phagocytosis escape, and subsequent clearance from vascular system.32, 33 Until now, various membrane-mimicking nanoplatforms based on several inherent host cells in biological fluids (e.g., erythrocytes, leukocytes, platelets, etc), has been extensively developed to mimic the cell membrane functions during many essential physiological processes such as the specific cell-cell interactions, intercellular recognition, adhesion as well as communication.34-36 Moreover, considering the specific membrane immunogenic antigens on various bacteria and viruses, the pathogen-mimicking nanoplatforms are also emerging as versatile vehicles to study the complex relationships between host immune system and invasive pathogens.37, 38

Figure 1. Development of biomimetic membrane-cloaked nanoplatforms inspired by the natural entities in biological fluids ranging from inherent host cellular structures (erythrocytes, leukocytes, platelets and exosomes) to invasive pathogens (bacteria and viruses).

In this review, we summarized recent advances of membrane-cloaked nanoplatforms to



mimic the natural entities in biological fluids ranging from inherent host cells (e.g., erythrocytes, leukocytes, platelets and exosomes) to invasive pathogens (e.g., bacteria and viruses) based on cell-membrane-mimicking and pathogen-mimicking strategies (Figure 1). These approaches provide excellent means to in-depth exploration of the detailed information regarding how nanomedicine interact with their surrounding environments and how to optimize their structures for improved theranostics in vivo. The last but not least, we also discussed the potential challenges and prospectives of these biomimetic membrane-cloaked nanoplatforms for their future development.

1. Erythrocyte-derived nanoplatforms Typically, the specific interactions of nanomedicine in many physiological processes play significant roles in their biological activities and therapeutic outcomes in living systems, including how to escape undesired phagocytosis and clearance by the host immune system and how to localize at the targeted pathological regions without side effects.39-41 In line with these factors, the erythrocytes, commonly known as red blood cells (RBCs), may act as a valuable model for the nanomedicine to explore and mimic their specific properties in vivo.42-44 Normally, RBCs are capable of serving as oxygen carriers throughout the body with prolonged circulation time (~ 120 days) in the vascular system.45 Moreover, the RBCs can easily escape the phagocytic immune cells-controlled clearance and degradation through the expression of several biomarkers on cell membrane including “don’t eat me” markers CD47 and signal-regulatory protein α (SIRPα) receptors.46 Such remarkable properties of RBCs suggest a promising strategy allowing traditional nanoparticles to achieve long circulation time and specific membrane functions for potential utilizations in living animals.47,

48

For example, RBCs-mimicking nanoparticles have been

designed by Zhang’s group for the development of novel biomimetic and long-circulating nanoplatforms based on their great biocompatibility and limited immunogenicity.49 They provided a smart strategy to fabricate RBCs membrane-camouflaged nanoparticles (RBCs-NPs) by two steps: RBCs membrane vesicle extrusion and vesicle-nanoparticle fusion (Figure 2A). Briefly, the isolated RBCs from whole blood underwent membrane rupture using hypotonic treatment to remove their intracellular components, and the emptied RBCs were washed and extruded through porous membranes to create erythrocyte-derived vesicles. The final core-shell structure of


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RBCs-NPs were achieved by fusing the RBCs vesicles with carboxyl-terminated PLGA nanoparticles via mechanical extrusion.50 Moreover, similar levels of protein content and expression of CD47 were demonstrated on RBC-NPs compared with native erythrocytes, and superior circulation half-life (39.6 h) was also achieved for RBC-NPs than that in conventional polyethylene glycol (PEG) modified nanoparticles (15.8 h) in mice. These results strongly indicated that RBCs-NPs could effectively prolong the circulation time in blood and mimic the specific membrane functions in living conditions. Furthermore, towards the biomedical applications of erythrocyte-derived nanoparticles, excellent selectivity is another desirable feature that promises minimization of off-target side effects for effective diseases diagnosis and therapeutics.51 So far, various chemical functionalization methods have been employed to modify nanoparticles with targeting ligands for their specific binding with overexpressed antigens (e.g., carbohydrates, proteins, etc) on the cell membranes at diseased sites.52-54 In order to non-disruptively integrate targeting ligands on the surface of RBCs-NPs, a lipid insertion strategy, which tethers targeting ligands to lipid molecules for RBC membranes insertion, was recently developed based on the intrinsic fluidity and dynamic conformation of the phospholipid bilayer of cell membrane (Figure 2B).55 This approach could not only allow for the membrane functionalization of various targeting ligands at different molecular weights from small-molecule folate (441 Da) to macro-molecule nucleolin-targeting aptamer AS1411 (9000 Da), but also achieve the adjustability of ligand density by controlling the lipid-tethered ligand input, which hold great promise to improve the selectivity of biomimetic nanoplatforms with reduced off-target side effects. Encouraged by these promising pioneer studies, similar RBCs-membrane-derived approaches have been applied in many other nanostructures including polymer nanoparticles,56 AuNPs,57 mesoporous silica nanoparticles,44 upconversion nanocrystals,58 and magnetic nanomaterials.59 All these RBCs-NPs hold unique capabilities to evade macrophage uptake and avoid immune clearance

in

living

systems.

Interestingly,

by

taking

advantages

of

their

specific

membrane-antigens interaction, RBCs-NPs have recently been employed as a biomimetic nanosponge to clear poisonous pathological antibodies and toxins in vivo.60-62 For instance, Zhang et al. demonstrated that RBCs-NPs could act as nanosponges to arrest membrane damaging staphylococcal alpha-hemolysin (α-toxin) in the bloodstream and to divert them away from their



cellular targets.60 In a mouse model, the nanosponges could prevent toxin-mediated haemolysis and reduce their toxicity by neutralization, which exhibited remarkable improvement of the survival rate in toxin-challenged mice (Figure 2C). Similarly, Zhang et al. also reported that the RBCs-NPs could abrogate the effect of pathological antibody-induced anaemia disease in which the immune system produces autoantibodies to attract healthy erythrocytes.61 Different from the conventional immune suppression drugs, the RBCs-NPs could serve as an alternative target for pathological antibody to protect healthy erythrocytes from macrophage phagocytosis (Figure 2D). These innovative studies clearly demonstrated that erythrocyte membrane-derived nanoparticles represented as promising therapeutic nanoplatforms for the broad range of biomedical applications on the basis of their multifaceted interactions with innate immune system in living animals.

Figure 2. Schematic illustration of erythrocyte-derived nanoplatforms. (a) RBCs-NPs fabrication procedures and TEM image. Scale bar: 50 nm. (b) Formation of targeted RBCs-NPs with lipid-tethered ligands. (c) Biomimetic nanosponges (right) and mechanism for neutralizing α-toxins (left). (d) Pathological antibodies opsonizing healthy RBCs for extravascular hemolysis via phagocytosis (left) and RBCs-NPs protecting RBCs by neutralizing antibodies (right). (Reprinted with permission from refs 49, 55, 60, and 61. Copyright 2011 and 2014 American Chemical Society, 2013 Nature Publishing Group, and 2012 Royal Society of Chemistry.)

2. Leukocytes-derived nanoplatforms


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Leukocytes, also known as white blood cells, are inherent cells in immune system to protect the living body against both infectious diseases and foreign invaders.63, 64 When the body tissues are damaged by infection or injury with inflammatory response generation, leukocytes are recruited from the bloodstream to the inflammation sites to effectively kill the pathogens and remove them by phagocytosis.65,

66

During this physiological process, the specific surface

interactions between leukocytes and endothelia play crucial roles in the recruitment of immune cells at the targeted disease regions, owing to the overexpression of endothelial adhesion molecules (e.g., integrins) to selectively bind with ligands expressed on leukocytes surface (such as selectins).67-69 Therefore, in order to mimic the membrane functions of leukocytes, a variety of bioinspired nanoplatforms have been constructed to explore the underlying mechanisms of leukocyte-endothelial interactions during the inflammatory response.25, 70-73 Basically, the initial investigations to endow nanoparticles with the intrinsic features of leukocytes mainly rely on the surface functionalization with target ligands.72, 74 For example, by modification the polymersome nanoparticles surface with specific leukocytal carbohydrate ligand (sialyl Lewisx), Hammer et al. demonstrated that this promising leuko-polymersome could firmly adhere to cell surfaces coated with the inflammatory adhesion molecules including P-selectin and activated β2-integrin (LFA-1, Mac-1, ICAM-1),74 which indicated significant effects to the kinetic and mechanical properties of leukocyte-endothelial rolling interactions. Despite the controllable physical and chemical parameters (e.g., size, component, surface ligands functionalization, homogeneity, etc) of the proposed strategy, it is still highly demanding to reproduce the integrality and complexity of leukocyte membrane.75,

76

In recent years,

researchers have considered the possibility for the efficient manipulation of the integrated leukocyte membrane to enable the transfer of several significant leukocyte markers on the surface of nanoparticles, including superior endothelial adhesion molecules (e.g., LFA-1, Mac-1, etc) and “self-recognition” proteins (e.g., CD45, CD47, etc) for long circulation.77, 78 For instance, Tasciotti et al. successfully integrated leukocyte plasma membrane onto nanoporous silicon (NPS) platform as hybrid leukocyte-like vectors (LLVs), which possessed specific leukocytes properties including biomarkers (CD45 and CD3z) and antigens (LFA-1 or CD11a) on the vector surface (Figure 3a).77 Importantly, the promising LLVs have the potential to recognize and communicate with endothelial cells through receptor-ligand interactions in an active and non-destructive manner



(Figure 3b), which could effectively improve the accumulation in tumor regions for further cancer therapy. Moreover, Zhang et al. demonstrated that grapefruit-derived nanovectors (GNV) coated with activated leukocytes membranes (IGNVs) could significantly enhance their endothelial cells transmigration capability at inflammatory sites, and further effectively inhibit tumor growth after encapsulation of doxorubicin (Dox) in IGNVs (Figure 3c).78 Intestinally, the targeted homing properties of IGNVs toward inflammatory tumor tissues could be blocked by some chemokine receptors including LFA-1 and CXCR2, indicating that these receptors play key roles in the recruitment and migration of leukocytes into inflamed regions. These relevant studies demonstrated that leukocytes-derived nanoparticles supply a versatile technique to explore the detailed processes of leukocyte-endothelial interactions during the inflammatory response in living system.

Figure 3. Schematic illustration of leukocytes-derived nanoparticles. (a) LLV structure and possible interactions between the functional groups on NPS surface and membrane phospholipids. (b) TEM (top) and SEM (bottom) images of bare NPS (left) and leukocyte-derived NPS (LLV) (right). Scale bars: 100 nm (TEM) and 1 mm (SEM). (c) Synthesis procedures of IGNVs for


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targeted homing of therapeutic drugs to inflammatory sites (left). (Reproduced with permission from ref. 77 and 78. Copyright 2013 Nature Publishing Group, and 2015 American Association for Cancer Research.)

3. Platelet-derived nanoplatforms As circulating sentinels in the bloodstream, platelet (also known as thrombocytes), is a key component in hemostasis and thrombosis during blood vessel injuries, which also performs significant functions in the development of lymphatic vasculature and mediation of innate or adaptive immune responses.79-81 Moreover, platelet involves in the pathological processes of multiple health issues including cancer, inflammation and infection, which can act as key role to mediate the platelet-cell interactions and their behaviors.82-84 However, extensive understanding of the detailed mechanisms and significant roles of platelets in these pathophysiological processes remain under unclear.85 Fortunately, recent studies have demonstrated the outstanding merits of platelets-mimicking nanoparticles for the explorations of various pathological pathways, including phagocytosis escape, immune system activation, and selective adhesion to damaged vasculatures and tumor tissues.86, 87 Until now, several approaches have been adopted to integrate platelets with various types of nanoparticles for the purpose of development of platelet-mimicking nanoplatforms. One initial strategy is to transfer platelet-derived surface moieties (e.g., proteins, glycans, etc) with specific functions to synthetic liposome nanoparticles (plateletsomes). For example, by modifying the liposome bilayer moieties which contained over fifteen kinds of platelet membrane glycoproteins, such as GPIb, GPIIb-IIIa and GPIV/III, Renzulli et al. reported a smart plateletsome with great hemostatic efficacy that presented a greater reduction (67% decrease) of tail bleeding in a thrombocytopenic rat model.88 Moreover, in order to exploit the specific interactions of receptors on the surfaces of platelets for targeting liposomes delivery, Marchant et al. modified an arginine-glycine-aspartic (RGD) peptide as a model ligand to target the integrin GPIIb-IIIa on activated platelets, which indicated that the peptides are capable of directing liposomes to receptors expressed on pathologically stimulated vascular territories.89 Despite the expected results in hemostasis and targeted payloads delivery presented by artificial plateletsomes, it is still a challenging task to replicate the flexible shape and highly complex platelet-cell interactions.90-92 In order to fully reserve the integrality of platelets, recent



studies indicated the development of biomimetic nanoparticles that combined the plasma membrane of platelets with various functional nanostructures. For instance, Zhang et al. developed a smart strategy by utilizing platelet membrane-cloaked PLGA nanoparticles (PNPs) for the specific clearance of anti-platelet antibodies in blood for effective treatment of immune thrombocytopenia (Figure 4a).93 The PNPs could act as decoys to strongly bind with pathological anti-platelet antibodies and subsequently neutralize them with considerable therapeutic efficacy for immune thrombocytopenia purpura in a murine model. Furthermore, they also reported the PNPs which endowed the nanoplatform surface with great integrity of platelets for the adherence of several disease-relevant substrates (Figure 4A).94 The resulting PNPs contained specific integrin components (e.g. αIIb, α2, β1, etc), transmembrane proteins (e.g. GPIbα, GPIV, CLEC-2, etc) and immunomodulatory antigens (e.g. CD47, CD55, CD59, etc), which could selectively adhere to the pathogens in damaged vasculatures of living animals. Moreover, enhanced therapeutic efficiency was determined to inhibit the growth of neointima in a coronary restenosis rat model by loading with docetaxel (Dtxl) and vancomycin (Van), which presented a multifaceted approach in developing effective nanoplatform for disease-targeted treatment. Such unique approaches based on platelet-derived nanoplatforms provided promising feasibility to fabricate the investigations of platelet-cells interactions in complicated pathophysiological processes including hemostasis, inflammation and infection in living conditions.

Figure 4. Platelet-derived nanoplatforms. (a) Scheme of PNPs preparation and activations as


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decoys to neutralize pathological anti-platelet antibodies for the treatment of immune thrombocytopenia. (b) (Left) H&E-stained arterial cross-sections of normal (top) and zoomed-in (bottom) tissues in a rat model of coronary restenosis at different treatment groups: baseline, Dtxl-loaded PNPs, PNPs, and Dtxl. I: intima; M: media. Scale bar: 200 mm (top), 100 mm (bottom). (Right) SEM images of MRSA252 bacteria at different groups. Scale bar: 1 µm. (Reproduced with permission from ref. 93 and 94. Copyright 2016 Elsevier and 2015 Nature Publishing Group.)

4. Exosome-derived nanoplatforms Exosomes, one type of intrinsic cell-derived small membrane vesicles usually with diameter range of 40-100 nm, can be secreted by most cell types in biological fluids.95, 96 Typically, the surface of exosomes consists of different kinds of biological components, such as chaperone proteins, adhesion molecules, and metabolic enzymes,97, 98 which exert their biological effects in a highly diversified manner, including activation of targeted cell surface receptors via protein-ligand interactions, merging of the membrane contents with the recipient cell membrane, or direct delivery of proteins, mRNA and lipid into recipient cells.99-101 Most of these features are determined by their specific surface proteins expression originating from parent cells.102,

103

Therefore, exosomes have been well recognized as an attractive nanoplatform for extensive biomedical applications due to their versatile and alterable membrane functions.104-107 For example, Wood et al. recently produced dendritic cells-derived exosomes for targeted delivery of short interfering RNA (siRNA) into the mouse brain for Alzheimer’s disease treatment (Figure 5A).106 In order to reduce the immunogenicity and achieve targeting effect, the dendritic cells were engineered to produce natural exosomes with membrane protein (Lamp2b) expression for selective fusion with neuron-specific RVG peptide. Upon loading exogenous siRNA through electroporation, the RVG-targeted exosomes could effectively deliver GAPDH siRNA to neurons, microglia and oligodendrocytes in the mouse brain after intravenous injection. Moreover, efficient mRNA (~ 60%) and protein (~ 62%) knockdown of a therapeutic target in Alzheimer’s disease (BACE1) were determined in vivo, which clearly demonstrated the effective therapy effects mediated by siRNA delivery nanoplatform with modification of exosome. Furthermore, Kang et al. also prepared dual-functional exosome-based drug delivery vehicles based on superparamagnetic



nanoparticle clusters for effective tumor treatment.107 With strong superparamagnetic property under an external magnetic field, the drug-loaded exosomes could be efficiently accumulated at desired tumor regions for significant inhibition of tumor growth in living animals. This strategy endowed the exosomes with magnetism and could thus advance the potential usage of exosomes in vivo. In spite of the promising perspectives of exosomes in biological sciences, so far, how to rapidly produce, isolate and purify exosomes in sufficient amounts remains a technical challenge that requires more research efforts involved.108,

109

Moreover, natural exosomes usually have

complicated surface components, which may come up with potential concerns to interfere the exosome-cell interactions during long-distance intercellular communication and targeted payload delivery.110, 111 To address these issues, the synthetic exosomes-like nanoparticles, which combine desired membrane proteins with phospholipid bilayer on the surface of artificial exosomes, have been developed in recent years.112-115 For instance, by utilizing biomimetic synthesis strategies, Liu et al. presented biofunctionalized liposome-like nanovesicles (BLNs) that are capable of artificially encapsulating two different kinds of tumor targeting moieties for effective drug delivery and cancer therapy in living mice (Figure 5B).113 Upon genetic engineering with human epidermal growth factor (hEGF) or anti-HER2 affibody as targeting ligands, the BLNs exhibited higher biological activities and selectivity towards EGF receptor-overexpressing cancer cells, and enhanced therapeutic outcomes than clinically approved liposomal-Dox in HER2-overexpressing BT474 tumor xenograft models. In addition, Gho et al. also reported exosome-mimetic nanovesicles with anticancer drug loading for targeted delivery in chemotherapy of cancer.114 The hybrid nanovesicles were prepared through breakdown of monocytes or macrophages by utilizing a serial extrusion with filters of different pore sizes. Interestingly, compared with traditional exosomes, these nanovesicles presented 100-fold higher production yield and exhibited excellent targeting capability by mimicking the topology of membrane proteins. Moreover, enhanced cell death and tumor growth


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Figure 5. Schematic illustration of exosome-derived nanoplatforms. (a) Preparation procedures of targeted exosomes for gene delivery. (b) Fabrication of exosome-like nanovesicles (BLNs) and their excellent targeting ligands-mediated affinity to the EGFR- or HER2-overexpressing tumor cells. (Reproduced with permission from ref. 106 and 113. Copyright 2011 Nature Publishing Group and 2017 John Wiley & Sons).

inhibition without toxic side effects have also been identified in living mice, clearly suggesting that the bioengineered nanovesicles could serve as novel exosome-mimetics with selective tumor affinity for enhanced treatment. These simplified exosomes nanostructure not only could be manufactured in a massive production manner through standard technology in industry, but they also provide desired surface functionalization method to achieve specific investigation of exosome-cell interactions in vitro and in vivo.

5. Bacterial-mimicking nanoplatforms It is well-known that there are a variety of microbes (e.g., bacteria, viruses, fungi, and other tiny organisms, etc) exist throughout the human body, which can definitely act as essential components of immunity and functional entity to influence fundamental metabolism and modulates cell host-microbes interactions in living systems.116-118 As one type of important microbes, bacterial species are actually of great practical interests to human beings and they are essential for normal body functions including digestion and immune responses. In general, a majority of bacteria are harmless owing to the protective effects of innate immune system, even some are beneficial particularly in the gut flora.119, 120 While, several kinds of extraneous bacteria are indeed pathogenic and induce various infectious diseases, including cholera, anthrax,



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tuberculosis and syphilis.121-123 Normally, the diverse bacterial surface components play critical roles in the pathogenesis of infectious disease since they mediate the specific activities of bacteria-cell interactions in living conditions, including colonize tissues, resist phagocytosis and active

immune

responses.124,

125

Despite

these

attractive

features,

the

excellent

bacterial-mimicking systems that can avoid the pathogenicity of living bacteria as well as preserve the integrality of bacterial membrane, are highly desirable in recent decades.126 Considering the promising ability of nanoparticles to mimic the key aspects of cellular membrane aforementioned, various bacterial-mimicking nanoparticles have been proposed in recent years for biomedical applications including the development of antibacterial vaccines and targeted delivery vehicles.127-131 For instance, by using Escherichia coli as a model pathogen, Zhang et al. developed a unique bacterial membrane-cloaked gold nanoparticle (BM-AuNPs) as an exciting and robust antibacterial vaccine (Figure 6a).130 The bacterial outer membrane vesicles (OMVs) were collected and further coated on the surface of small AuNPs (~30 nm). After subcutaneous injection, the BM-AuNPs induced rapid activation and maturation of dendritic cells in lymph nodes of vaccinated mice. Interestingly, the BM-AuNPs presented a higher efficacy to elicit bacterium-specific B-cell and T-cell responses in the vaccinated animals than those elicited by OMVs only, indicating that the synergistic action of bacterial membranes and AuNPs cores could benefit each other for enhanced immune responses. These results clearly showed that the synthetic nanoparticles with natural bacterial membranes modification holds great promise for fabricating effective antibacterial vaccines. Moreover, so far, the bacterial-mimicking strategy has also been applied to establish the effective delivery vehicles towards enhanced targeting of diseases regions.132-135 For instances, Gho et al. engineered one novel nanovesicle system by utilizing bacterial protoplast (a type of cells with wall structure removed) as a unique cargo for targeted delivery (Figure 6b).133 After removing the toxins in the outer wall of bacteria, the bacterial protoplast-derived nanovesicles (

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Figure 6. Schematic illustration of bacterial-mimicking nanoplatforms. (a) Modulation of antibacterial vaccines via BM-AuNPs. (b) TEM image and stability of BM-AuNPs (top); CD11c+ and INF-γ expressions from activated dendritic cells and T cells in vivo (bottom). (c)

EGF

PDNV

production from EGF expressing bacteria. (Reproduced with permission from ref. 130 and 133. Copyright 2016 American Chemical Society and 2017 Elsevier.)

fabricated by serial extrusions on the basis of nano-sized membrane filters. The PDNV could selectively deliver chemotherapeutics (e.g., Dox) to tumor tissues via receptor-mediated interactions through the specific surface expression of tumor-targeting moieties, such as epidermal growth factor (EGF) etc. In vivo experiments further indicated that the drug-loaded PDNV could not only efficiently inhibit the tumor growth, but also reduce the chemotherapeutics-induced adverse effects in heart after systemic administration to mice. These innovative studies demonstrated that bacterial-mimicking nanomaterials provide the great potential to systematically understand the complicated bacteria-cell interactions during the treatment of diverse infectious diseases.

6. Virus-mimicking nanoplatforms As a small infectious species, virus can replicate itself only when it invades into the host including animals, plants, bacteria and other organisms.136,

137


Naturally pathogenic viruses


possess the intrinsic ability to avoid immune system recognition and inject their genetic material (e.g., DNA or RNA) into a host for self-replication, which will cause severe infectious inflammation (e.g., AIDS, SARS, Ebola virus disease, etc) and eventually result in the death of the host.138-140 During the invasion processes, the outer membrane of virus such as capsid (a protein coat) or envelope (lipid bilayer) plays a significant role in viral infection, including cell attachment and entry, gene release and assembling of newly formed viruses.141-143 Therefore, the detailed understanding of the intricate virus-cell interactions will ultimately provide more information for the design of innovative and effective therapeutics against viral infection. So far, various viral vectors such as adenoviruses, retroviruses and lentiviruses etc, have been utilized for successful clinical applications in the treatment of adenosine deaminase deficiency and X-inked severe combined immunodeficiency.144-146 However, considering the case that these viral vectors are pathogenic and can be derived from viruses in natural infection, substantial concerns still occur regarding their potential issues in safety and immunogenicity.147 In order to achieve the benefits of viruses while greatly minimizing these potential issues of introducing pathogenic genes, extensive research efforts have been engaged to design an initial generation of virus-like nanoparticles (VNPs) and virosomes, which are self-assembled nanoparticles and could mimic the capsid and envelope structures with incorporation of functional surface glycoproteins in real viruses.148-152 For example, Sainsbury et al. reported the recombinant of a novel VNPs based on the capsid assembled by bluetongue virus structural proteins (VP3 and VP7) from plant leaves (Figure 7a).152 The VNPs presented specific capability to bind with cell surface receptors (e.g., αvβ3/β5 integrins) by integrating with cyclic RGD peptide, which could act as an attractive vehicle for effective payloads delivery including therapeutic drugs, contrast agents, proteins and siRNA towards cancer treatment. Encouraged by these successful investigations, scientists developed novel nanoparticles that mimic various natural features of viruses (e.g., surface antigens recognition, cytoplasmic capsid


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Figure 7. Schematic illustration of virus-mimicking nanoplatforms. (a) Synthesis and isolation procedures of plant-based VNPs (top); recombined structure and TEM image of VNPs (bottom) assembled by virus proteins (VP3 and VP7). Scale bar: 200 nm. (b) Chemical structure of peptide and TEM images of self-assembled capsid with nanoribbon and nanococoon structures in the absence and presence of DNA as templates. Scale bar: 100 nm. (Reproduced with permission from ref. 152 and 153. Copyright 2014 and 2017 American Chemical Society.)

assembly, immune system escape, etc) to explore the virus-cell interactions through the specific surface modifications of these assembled carriers.153-155 For example, inspired by viral capsid protein structures, Ni and Chau recently constructed a biomimetic capsid assembled by synthetic peptide with specific nanoribbon and nanococoon shapes and striped surface patterns (Figure 7b).153 The rational design of this smart peptide contained different segments for DNA binding and β-sheet assembling, which offered the capabilities of artificial capsid with excellent stability, low permeability and resistance to enzyme digestion for gene protection. More importantly, this biomimetic strategy could regulate and control the properties of synthetic capsid by introducing



Page 18 of 37

diverse functional groups into assembling blocks, which therefore produced a feasible model to Membrane

Corea

sources

Size

Payloadb

(nm)

Loading

Targeting

Circulation

%ID/g in

capacity

moietiesc

time (t1/2, h)

org-ansd (24 h)

Ref.

understand the peptide/DNA interaction during capsid encapsulation process. These promising studies suggested that virus-mimicking nanoparticles could provide more beneficial information for effectively pharmaceutical development against viral infection and detailed understanding of virus activities in living animals.

Conclusion and perspectives Currently, extensive nanomedicine hold great potential for the precise diagnosis and effective therapeutics of various human diseases in clinical practice. However, a detailed understanding regarding how nanomedicine interact with the intricate environment in complex living systems, still remains challenging. To this end, inspired by the diversified membrane structures and functions of natural prototypes, relevant researches have increased exponentially for the development of membrane-mimicking nanoplatforms, which endowed the abiotic nanomaterials with specific biological functionalities to investigate the complicated interactions and activities of nanomedicine in human bodies. In this review, we focused on the strategies established recently for the development of membrane-cloaked nanoplatforms derived from inherent host cells (e.g., erythrocytes, leukocytes, platelets and exosomes) and invasive pathogens (e.g., bacteria and viruses), mainly attributed to their versatile membranes properties in biological fluids. The representative examples of different kinds of biomimetic membrane-cloaked nanoplatforms in living system are summarized in Table 1. Despite the widely exploitation of diverse membrane-mimicking strategies in recent decades, there is still a long way toward conducting the c l i n i c a l

t r i a l

o f

t h i s

r e s e a r c h

f i e l d .

Table 1. Representative examples of biomimetic membrane-cloaked nanoplatforms in living system.


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Erythrocytes

PLGA

80

––

––

––

39.6

L: 39, S: 26,

49

G: 14, B: 10 MSNs

Bismuth

108

56

Ce6

21%

Dox

39%

Bi

70%

––

11.5

GNV

FA

17.1

200

Dox

75%

CXCR2

––

120

PTX

76%

LFA-1

––

115

DM1

96%

α4β1-

PLGA

nanogel

113

Dtxl

2.1%

surface-

200

Van

4.0%

glycans

121

Dox

––

TRAIL,

4.9

Exosomes

88

siRNA

25%

Lamp2b

78

L: 48, B: 12,

157

L: 62, G: 21,

158

K: 9, S: 6 33.2

L: 42, S: 28,

94

K: 4, D: 17 32.6

P-selectin ––

L: 18, S: 14,

K: 13, T: 7

integrin Platelets

156

K: 7, G: 8, T: 7

CD45 liposome

L: 34, S: 19, K: 7, T: 9

LFA-1 ––

41

G: 15, T: 18

(Bi) NPs Leukocytes

L: 40, S: 13,

L: 19, S: 5, K:

159

12, G: 7, T: 53 ––

L: 19, S: 16,

106

M: 18, H:17 ––

105

ICG

>70%

Dox Bacteria

––

42

Dox

hEGF

7.2

––

113

––

L: 7, S: 14, K:

133

anti-HER2 40%

hEGF

6, G: 6, T: 62

Viruses

––

90-133

siRNA

15%

anti-HER2

––

––

160

––

50-150

HA

6.5%

HPV16 L2

––

L: 45, S: 42,

151

K: 12 ––

33

Dox

3.9%

RGD

––

L: 14, S: 4,

161

K: 24, T: 37 a

MSNs: mesoporous silica nanoparticles.

b

Ce6: chlorin e6, PTX: paclitaxel, DM1: emtansine, ICG: Indocyanine green, HA: hemagglutinin.

c

FA: folic acid, CXCR2: CXC chemokine receptor 2, LFA-1: Lymphocyte function-associated antigen 1 (LFA-1), TRAIL: tumor necrosis factor (TNF)-related apoptosis inducing ligand, HPV: human papillomavirus, RGD: Arg-Gly-Asp tripeptide.

d

L:liver, S:spleen, K:kidney, G:lung, B:blood, T: tumor, D: denuded artery, M: muscle, H:heart.

For example, these “cloaking” strategies could effectively endow various nanoparticles with specific advantages of diverse biological membranes, such as long circulation time in blood (erythrocytes), great selectivity at inflamed endothelial regions (leukocytes) and excellent capacity



to evade immune system recognition (viruses). However, numerous works are greatly expected to formulate these bioinpired nanoplatforms by avoiding their undesirable shortcomings, including complex synthetic and purification routes (platelets), lack of standardized protocol for preparation and isolation in sufficient amounts (erythrocytes and exosomes), and potential concerns regarding safety and immunogenicity in human body (bacterial and viruses) (Table 2). Therefore, great challenges still remain in this research area which require extensive exploitation in near future.

Table 2. Advantages and disadvantages of various biomimetic membrane-cloaked nanoplatforms. Membrane types

Advantages

Disadvantages

Erythrocytes

Long circulation time in blood

Time-consuming purification methods

Simple approaches for membrane

Lack of standardized protocol for preparation,

functionalization

purification and storage in sufficient amounts

Great selectivity at specific disease regions

Inadequate to reproduce the integrality and

and regulation of inflammatory response

complexity of leukocyte membrane

Favorable properties in treating hemostasis,

Complex synthetic and purification routes

hemorrhage and targeted payloads delivery

Limited assessment of immunogenic potential

Promising candidate for payload delivery

Lack of standardized methods to rapidly produce,

Long-distance cell-to-cell communications

isolate and purify exosomes in sufficient amounts

Great antibacterial vaccines and targeted

Potential concerns regarding safety and

delivery vehicles

immunogenicity

Excellent capacity in cellular targeting, entry

Potential concerns regarding safety and

and avoiding immune system recognition

immunogenicity

Leukocytes

Platelets

Exosomes

Bacteria

Viruses

First of all, although these biomimetic strategies based on various cell membranes and pathogens have been widely established in recent years, it is still difficult to maintain the integrality and functionality of natural entities due to the requirement of multiple labor-intensive processes during the fabrication of these membrane-mimicking nanoparticles, such as genetic engineering or prolonged ex vivo hypotonic treatment.49, 149 For example, the surface integrality of RBCs could be compromised during ex vivo producing of RBC-coated nanoparticles, which may result in a decreasing circulation time and rapid clearance by immune system.8, 76 Therefore, researchers should pay more attention to optimize the membrane extraction techniques and particle-membrane fusion procedures, which will minimize the structural alterations for more


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accurate investigations of the relationships between the interfaces of nanotechnology and biology. Furthermore, even though several rational designs of membrane-cloaked nanoplatforms are inspired by natural biomoieties including living cells and pathogens, the potential immunogenicity of these biomimetic nanostructures may still occur as undesired side effects and safety concerns, especially for pathogen-mimicking nanoparticles.162 For example, a series of conformational changes of the membrane-anchored fragments (e.g., proteins, glycans, etc) might be occurred during the period of membrane extraction or fusing with nanoparticles, which could be recognized as invader to activate immune response.163 Significantly, it is worth noting that some certain degrees of immunogenicity could be beneficial to human health when the pathogen-mimicking nanoparticles are designed as vaccines to stimulate the adaptive immune responses. However, the potentially immunogenic components of pathogens that may induce unexpected immune response/reaction in vivo, must be removed or inactivated, and their biosafety should be thoroughly addressed by the examinations in preclinical studies.164 In summary, the biomimetic membrane-cloaked nanoplatforms by integrating the diversified properties of various biological membranes and nanomaterials, provide a bright perspective for the investigations regarding the performance of nanomedicine within the intricate environment during diverse physiological and pathological processes in living systems. Along with all the innovative studies in these research areas, we believe that these bioinspired strategies conjugated with attractive features of nanomaterials will promote the development of efficient and precise nanomedicine and finally have a promising outlook to benefit human health.

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected] Notes The authors declare no competing financial interest.

ACKNOWLEDGMENTS The authors acknowledge the financial supports by NTU-AIT-MUV NAM/16001, RG110/16 (S), Merlion 2017 Program (M4082162), JSPS-NTU Joint Research (M4082175) and (RG 35/15)



awarded in Nanyang Technological University, Singapore and National Natural Science Foundation of China (NSFC) (No. 51628201).

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Recent Advances of Membrane-Cloaked Nanoplatforms for

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