Recent advances of membrane-cloaked nanoplatforms for biomedical

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Cite This: Bioconjugate Chem. XXXX, XXX, XXX−XXX

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 great potential for precise diagnosis and effective therapeutics of various human diseases in clinical practice. However, a detailed understanding regarding how nanomedicine interacts 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 cloaking nanosized platforms, have increased exponentially. By taking advantage 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 biomoieties such as lipids, glycans, and even cell and bacteria membrane components, which endow 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 summarize the strategies established recently for the development of biomimetic 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 membrane properties in biological fluids. Meanwhile, the promising biomedical applications based on nanoplatforms inspired by diverse moieties, such as selective drug delivery in targeted sites and effective vaccine development for disease prevention, have also been outlined. Finally, the potential challenges and future prospects of the biomimetic membranecloaked nanoplatforms are also discussed.

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INTRODUCTION Currently, the remarkable progress of nanomedicine based on extensive usage of nanotechnology has received considerable interest for its potential in precise diagnosis and effective therapeutics of various diseases including cancer, cardiovascular disease, 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 progress in recent decades, a detailed understanding regarding how nanomedicine interacts with the intricate environment in living systems still remains a pressing and challenging goal.13−15 Many significant effects of structures in nanomedicine designed for their unique bioactivity and function, especially for their dynamic transport pathways in the 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© XXXX American Chemical Society

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 inherent properties to regulate diverse biological processes (e.g., growth, metabolism, immunity, etc.), which serve as a major source to motivate us in constructing biomimetic nanostructures for the investigation of nanomedicine bioactivities in vivo.22−24 Particularly, inspired by the diversified membrane structures and functions of these Special Issue: Biomimetic Materials Received: February 10, 2018 Revised: March 2, 2018 Published: March 6, 2018 A

DOI: 10.1021/acs.bioconjchem.8b00103 Bioconjugate Chem. XXXX, XXX, XXX−XXX

Review

Bioconjugate Chemistry

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 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 cell-controlled clearance and degradation through the expression of several biomarkers on the cell membrane including “don’t eat me” marker 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 utilization 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 membranecamouflaged nanoparticles (RBCs-NPs) in 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 RBCs-NPs was achieved by fusing the RBC vesicles with carboxyl-terminated PLGA nanoparticles via mechanical extrusion.50 Moreover, similar levels of protein content and expression of CD47 were demonstrated on RBCNPs 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, toward the biomedical applications of erythrocyte-derived nanoparticles, excellent selectivity is another desirable feature that promises minimization of off-target side effects for effective disease 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 nondisruptively integrate targeting ligands on the surface of RBCs-NPs, a lipid insertion strategy, which tethers targeting ligands to lipid molecules for RBC membrane 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 smallmolecule folate (441 Da) to macromolecule nucleolin-targeting aptamer AS1411 (9000 Da), but also achieve the adjustability of ligand density by controlling the lipid-tethered ligand input,

natural biomoieties, research activity on biomimetic membranes, especially for those cloaking nanosized 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 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 biomoieties such as lipids, glycans, and even cell and bacteria surface components.29−31 These hybridized nanoplatforms endow the abiotic nanomaterials with specific biological functionalities for the exploration of complicated interactions and activities of nanomedicine in living conditions, including immune response activation, phagocytosis escape, and subsequent clearance from the 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.) have been developed to mimic the cell membrane function 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 In this review, we summarize recent advances of membranecloaked 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-membranemimicking and pathogen-mimicking strategies (Figure 1).

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).

These approaches provide excellent means to in-depth exploration of the detailed information regarding how nanomedicine interacts with the surrounding environment and how to optimize their structures for improved theranostics in vivo. Last but not least, we also discuss the potential challenges and prospectives of these biomimetic membrane-cloaked nanoplatforms for future development. B


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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. LEUKOCYTE-DERIVED NANOPLATFORMS Leukocytes, also known as white blood cells, are inherent cells in the immune system that 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 leukocyte surfaces (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 of the polymersome nanoparticle surface with specific leukocytal carbohydrate ligands (sialyl Lewisx), Hammer et al. demonstrated that this promising leukopolymersome 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 the leukocyte membrane.75,76 In recent years, researchers have considered the possibility of efficient manipulation of the

which holds great promise to improve the selectivity of biomimetic nanoplatforms with reduced off-target side effects. Encouraged by these promising pioneer studies, similar RBCmembrane-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 RBCsNPs hold unique capabilities to evade macrophage uptake and avoid immune clearance in living systems. Interestingly, by taking advantage of their specific membrane−antigen 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 (αtoxin) in the bloodstream and to divert them away from their cellular targets.60 In a mouse model, the nanosponges could prevent toxin-mediated hemolysis and reduce their toxicity by neutralization, which exhibited remarkable improvement in survival rate of toxin-challenged mice (Figure 2c). Similarly, Zhang et al. also reported that the RBCs-NPs could abrogate the effect of pathological antibody-induced anemia 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 antibodies to protect healthy erythrocytes from macrophage phagocytosis (Figure 2d). These innovative studies clearly demonstrated that erythrocyte membrane-derived nanoparticles represented promising therapeutic nanoplatforms for the broad range of biomedical applications on the basis of their multifaceted interactions with innate immune system in living animals. C


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Figure 3. Schematic illustration of leukocyte-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 targeted homing of therapeutic drugs to inflammatory sites (left). (Reproduced with permission from refs 77 and 78. Copyright 2013 Nature Publishing Group, and 2015 American Association for Cancer Research.)

explore the detailed processes of leukocyte−endothelial interactions during the inflammatory response in living systems.

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 a nanoporous silicon (NPS) platform as hybrid leukocyte-like vectors (LLVs), which possessed specific leukocyte 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 nondestructive 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 leukocyte membranes (IGNVs) could significantly enhance their endothelial cell 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 leukocyte-derived nanoparticles supply a versatile technique to

3. PLATELET-DERIVED NANOPLATFORMS As circulating sentinels in the bloodstream, platelets (also known as thrombocytes) are key components in hemostasis and thrombosis during blood vessel injuries, and also perform significant functions in the development of lymphatic vasculature and mediation of innate or adaptive immune response.79−81 Moreover, platelets are involved in the pathological processes of multiple health issues including cancer, inflammation, and infection, acting in a 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 plateletmimicking nanoparticles for the exploration of various pathological pathways, including phagocytotic escape, immune system activation, and selective adhesion to damaged vasculature 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 contain over 15 kinds of platelet D


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Figure 4. Platelet-derived nanoplatforms. (a) Scheme of PNP preparation and activation as decoys to neutralize pathological antiplatelet 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 refs 93 and 94. Copyright 2016 Elsevier and 2015 Nature Publishing Group.)

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 ligand-mediated affinity to the EGFR- or HER2-overexpressing tumor cells. (Reproduced with permission from refs 106 and 113. Copyright 2011 Nature Publishing Group and 2017 John Wiley & Sons).

nanoparticles (PNPs) for the specific clearance of antiplatelet antibodies in blood for effective treatment of immune thrombocytopenia (Figure 4a).93 The PNPs could act as decoys to strongly bind with pathological antiplatelet antibodies and subsequently neutralize them with considerable therapeutic efficacy for immune thrombocytopenia purpura in a murine model. Furthermore, they also reported the PNPs which endow the nanoplatform surface with platelets for the adherence of several disease-relevant substrates (Figure 4b).94 The resulting PNPs contained specific integrin components (e.g., αIIb, α2, β1, etc.), transmembrane proteins (e.g., GPIbα, GPIV, CLEC2, etc.), and immunomodulatory antigens (e.g., CD47, CD55, CD59, etc.), which could selectively adhere to the pathogens in damaged vasculature 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 an effective nanoplatform for disease-targeting treatment. Such unique approaches based on platelet-derived nanoplatforms provided promising feasi-

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 liposome delivery, Marchant et al. modified an arginine-glycine-aspartic (RGD) peptide as a model ligand to target the integrin GPIIbIIIa 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 payload 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 preserve the integrality of platelets, recent studies have 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 utilizing platelet membrane-cloaked PLGA E


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

Furthermore, Kang et al. also prepared dual-functional exosome-based drug delivery vehicles based on superparamagnetic nanoparticle clusters for effective tumor treatment.107 With a 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 effort.108,109 Moreover, natural exosomes usually have complicated surface components, which may raise potential concerns to interfere with the exosome−cell interactions during long-distance intercellular communication and targeted payload delivery.110,111 To address these issues, synthetic exosome-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 activity and selectivity toward 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

bility to fabricate the investigations of platelet−cell interactions in complicated pathophysiological processes including hemostasis, inflammation, and infection in living conditions.

4. EXOSOME-DERIVED NANOPLATFORMS Exosomes, one type of intrinsic cell-derived small membrane vesicle usually with diameter range of 40−100 nm, can be secreted by most cell types in biological fluids.95,96 Typically, the surfaces of exosomes consist 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 protein 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 cellderived 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 a 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) was determined in vivo, which clearly demonstrated the effective therapeutic effects mediated by siRNA delivery nanoplatform with modification of exosome. F


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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 6c).133 After removing the toxins in the outer wall of the bacteria, the bacterial protoplast-derived nanovesicles (PDNV) could be fabricated by serial extrusions on the basis of nanosized 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 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 the heart after systemic administration to mice. These innovative studies demonstrated that bacterial-mimicking nanomaterials provide great potential to systematically understand the complicated bacteria−cell interactions during the treatment of diverse infectious diseases.

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 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 exosome nanostructures not only could be manufactured in a mass production manner through standard technology in industry, but they also provide desired surface functionalization methods 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) throughout the human body, which can definitely act as essential components of immunity and functional entities to influence fundamental metabolism and modulate cell host−microbe interactions in living systems.116−118 As one type of important microbes, bacterial species are actually of great practical interest to human beings, and they are essential for normal body functions including digestion and immune response. In general, a majority of bacteria are harmless owing to the protective effects of the innate immune system; some are even particularly beneficial in the gut.119,120 However, several kinds of extraneous bacteria are indeed pathogenic and induce various infectious diseases, including cholera, anthrax, 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 colonizing tissues, resisting phagocytosis, and activating immune responses.124,125 With 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 have become highly desirable in recent decades.126 Considering the promising ability of nanoparticles to mimic the aforementioned key aspects of the cellular membrane, various bacteria-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 AuNP cores could benefit each other for enhanced immune responses (Figure 6b). These results clearly showed that the synthetic nanoparticles with natural bacterial membrane modification hold great promise for fabricating effective antibacterial vaccines. Moreover, so far, the bacterial-mimicking strategy has also been applied to establish the effective delivery vehicles toward enhanced targeting of diseases regions.132−135 For instance,

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 selfreplication, 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 the virus such as the 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-linked severe combined immunodeficiency.144−146 However, considering the case in which 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 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 payload delivery including therapeutic drugs, contrast agents, proteins, and siRNA toward 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 assembly, immune system escape, etc) to G


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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 research has increased exponentially for the development of membranemimicking nanoplatforms, which endow 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 membrane 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 wide exploitation of diverse membrane-mimicking strategies in recent decades, there is still a long way toward conducting any clinical trials in this research field. 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 the human body (bacteria and viruses) (Table 2). Therefore, great challenges still remain in this research area which require extensive exploitation in the near future. 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 decreasing circulation time and rapid clearance by the immune system.8,76 Therefore, researchers should pay more attention to optimizing the membrane extraction techniques and particle−membrane fusion procedures, which will minimize the structural alterations for more 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 occurring during the period of membrane extraction or fusion with nanoparticles, which could be recognized as invaders 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

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 refs 152 and 153. Copyright 2014 and 2017 American Chemical Society.)

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 assembly, 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 diverse functional groups into assembling blocks, which therefore produced a feasible model to understand the peptide/DNA interaction during the capsid encapsulation process. These promising studies suggested that virus-mimicking nanoparticles could provide more beneficial information for effective pharmaceutical development against viral infection and detailed understanding of virus activities in living animals.

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CONCLUSION AND PERSPECTIVES Currently, extensive nanomedicine holds great potential for the precise diagnosis and effective therapeutics of various human diseases in clinical practice. However, a detailed understanding H


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Bioconjugate Chemistry Table 1. Representative Examples of Biomimetic Membrane-Cloaked Nanoplatforms in Living Systems membrane sources Erythrocytes

corea

Platelets

80

−−

MSNs

108 56

Ce6 Dox Bi

GNV

200

−−

loading capacity

targeting moietiesc

39.6

21% 39% 70%

−−

11.5

FA

17.1

Dox

75%

CXCR2 LFA-1

−−

120

PTX

76%

LFA-1 CD45

−−

liposome

115

DM1

96%

α4β1- integrin

4.9

PLGA

113 200 121

Dtxl Van Dox

2.1% 4.0% −−

surface- glycans

33.2

TRAIL, P-selectin Lamp2b

32.6

−−

88

−−

105

Bacteria

−−

42

Viruses

−− −−

90−133 50−150

−−

33

siRNA ICG Dox Dox

−−

circulation time (t1/2, h)

−−

nanogel Exosomes

payloadb

PLGA

Bismuth (Bi) NPs Leukocytes

size (nm)

25% >70%

%ID/g in organsd (24 h)

ref

L: 39, S: 26, G: 14, B: 10 L: 40, S: 13, G: 15, T: 18 L: 34, S: 19, K: 7, T: 9 L: 18, S: 14, K: 7, G: 8, T: 7 L: 48, B: 12, K: 13, T: 7 L: 62, G: 21, K: 9, S: 6 L: 42, S: 28, K: 4, D: 17 L: 19, S: 5, K: 12, G: 7, T: 53 L: 19, S: 16, M: 18, H:17 −−

49

−−

40%

hEGF anti-HER2 hEGF

7.2 −−

siRNA HA

15% 6.5%

anti-HER2 HPV16 L2

−− −−

Dox

3.9%

RGD

−−

L: 7, S: 14, K: 6, G: 6, T: 62 −− L: 45, S: 42, K: 12 L: 14, S: 4, K: 24, T: 37

41 156 78 157 158 94 159 106 113 133 160 151 161

a

MSNs: mesoporous silica nanoparticles. bCe6: chlorin e6, PTX: paclitaxel, DM1: emtansine, ICG: Indocyanine green, HA: hemagglutinin. cFA: 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. dL: liver, S: spleen, K: kidney, G: lung, B: blood, T: tumor, D: denuded artery, M: muscle, H: heart.

Table 2. Advantages and Disadvantages of Various Biomimetic Membrane-Cloaked Nanoplatforms membrane types

advantages

Erythrocytes

Long circulation time in blood Simple approaches for membrane functionalization

Leukocytes

Great selectivity at specific disease regions and regulation of inflammatory response Favorable properties in treating hemostasis, hemorrhage and targeted payloads delivery

Platelets Exosomes Bacteria Viruses

disadvantages

Promising candidate for payload delivery Long-distance cell-to-cell communications Great antibacterial vaccines and targeted delivery vehicles Excellent capacity in cellular targeting, entry, and avoiding immune system recognition

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.

Time-consuming purification methods Lack of standardized protocol for preparation, purification, and storage in sufficient amounts Inadequacy reproducing the integrality and complexity of leukocyte membrane Complex synthetic and purification routes Limited assessment of immunogenic potential Lack of standardized methods to rapidly produce, isolate, and purify exosomes in sufficient amounts Potential concerns regarding safety and immunogenicity Potential concerns regarding safety and immunogenicity

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.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Jun Lin: 0000-0001-9572-2134 Bengang Xing: 0000-0002-8391-1234 I


Review

Bioconjugate Chemistry Notes

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The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors acknowledge the financial support by NTU-AITMUV 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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