Recent Advances of Membrane-Cloaked Nanoplatforms for … · 2018-05-05 · nanoplatforms inspired by diverse moieties, such as selective drug delivery in targeted sites and eﬀective

Recent Advances of Membrane-Cloaked Nanoplatforms forBiomedical ApplicationsXiangzhao 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 surfacearea, nanomaterials often exhibit unusual physical and chemical properties,which have recently attracted considerable attention in bionanotechnology andnanomedicine. Currently, the extensive usage of nanotechnology in medicineholds great potential for precise diagnosis and effective therapeutics of varioushuman diseases in clinical practice. However, a detailed understanding regardinghow nanomedicine interacts with the intricate environment in complex livingsystems remains a pressing and challenging goal. Inspired by the diversifiedmembrane structures and functions of natural prototypes, research activities onbiomimetic and bioinspired membranes, especially for those cloaking nanosizedplatforms, have increased exponentially. By taking advantage of the flexiblesynthesis and multiple functionality of nanomaterials, a variety of uniquenanostructures including inorganic nanocrystals and organic polymers havebeen widely devised to substantially integrate with intrinsic biomoieties such as lipids, glycans, and even cell and bacteriamembrane components, which endow these abiotic nanomaterials with specific biological functionalities for the purpose ofdetailed investigation of the complicated interactions and activities of nanomedicine in living bodies, including their immuneresponse activation, phagocytosis escape, and subsequent clearance from vascular system. In this review, we summarize thestrategies established recently for the development of biomimetic membrane-cloaked nanoplatforms derived from inherent hostcells (e.g., erythrocytes, leukocytes, platelets, and exosomes) and invasive pathogens (e.g., bacteria and viruses), mainly attributedto their versatile membrane properties in biological fluids. Meanwhile, the promising biomedical applications based onnanoplatforms inspired by diverse moieties, such as selective drug delivery in targeted sites and effective vaccine development fordisease prevention, have also been outlined. Finally, the potential challenges and future prospects of the biomimetic membrane-cloaked nanoplatforms are also discussed.

■ INTRODUCTION

Currently, the remarkable progress of nanomedicine based onextensive usage of nanotechnology has received considerableinterest for its potential in precise diagnosis and effectivetherapeutics of various diseases including cancer, cardiovasculardisease, as well as neurological disorders,1−6 mostly owing tothe unique physical and chemical properties of diversenanomaterials in terms of the nanoscale size effect and highsurface-to-volume ratio.7−12 Despite the continuous progress inrecent decades, a detailed understanding regarding hownanomedicine interacts with the intricate environment in livingsystems still remains a pressing and challenging goal.13−15

Many significant effects of structures in nanomedicine designedfor their unique bioactivity and function, especially for theirdynamic transport pathways in the vascular system, clearance,phagocytic immune-mediated degradation, as well as thepotential binding sites of nanomedicine in living bodies, havenot yet been thoroughly elucidated.16−18 To this end, the well-

designed nanoplatforms are highly demanded as advancedbiotechnological tools to fully understand the detailedbehaviors of nanomedicine in complicated physiopathologicalprocesses including disease surveillance, sensitive diagnosis, andtargeted therapeutics.19−21

In fact, there are plenty of native prototypes (e.g., cells, virus,bacteria, etc.) with inherent properties to regulate diversebiological processes (e.g., growth, metabolism, immunity, etc.),which serve as a major source to motivate us in constructingbiomimetic nanostructures for the investigation of nano-medicine bioactivities in vivo.22−24 Particularly, inspired bythe diversified membrane structures and functions of these

Special Issue: Biomimetic Materials

Received: February 10, 2018Revised: March 2, 2018Published: March 6, 2018

Review

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natural biomoieties, research activity on biomimetic mem-branes, especially for those cloaking nanosized platforms, hasincreased exponentially in recent decades.25−28 So far, on thebasis of the flexible synthesis and multiple functionality ofnanomaterials, a variety of unique nanostructures includinginorganic nanocrystals (e.g., gold nanoparticles (AuNPs), etc.)and organic polymers (e.g., poly(lactic-co-glycolic acid)(PLGA) nanoparticles, etc.) have been widely devised tosubstantially integrate with intrinsic biomoieties such as lipids,glycans, and even cell and bacteria surface components.29−31

These hybridized nanoplatforms endow the abiotic nanoma-terials with specific biological functionalities for the explorationof complicated interactions and activities of nanomedicine inliving conditions, including immune response activation,phagocytosis escape, and subsequent clearance from thevascular system.32,33 Until now, various membrane-mimickingnanoplatforms based on several inherent host cells in biologicalfluids (e.g., erythrocytes, leukocytes, platelets, etc.) have beendeveloped to mimic the cell membrane function during manyessential physiological processes such as the specific cell−cellinteractions, intercellular recognition, adhesion, as well ascommunication.34−36 Moreover, considering the specificmembrane immunogenic antigens on various bacteria andviruses, the pathogen-mimicking nanoplatforms are alsoemerging as versatile vehicles to study the complex relation-ships between host immune system and invasive pathogens.37,38

In this review, we summarize recent advances of membrane-cloaked nanoplatforms to mimic the natural entities inbiological fluids ranging from inherent host cells (e.g.,erythrocytes, leukocytes, platelets, and exosomes) to invasivepathogens (e.g., bacteria and viruses) based on cell-membrane-mimicking and pathogen-mimicking strategies (Figure 1).

These approaches provide excellent means to in-depthexploration of the detailed information regarding how nano-medicine interacts with the surrounding environment and howto optimize their structures for improved theranostics in vivo.Last but not least, we also discuss the potential challenges andprospectives of these biomimetic membrane-cloaked nanoplat-forms for future development.

1. ERYTHROCYTE-DERIVED NANOPLATFORMS

Typically, the specific interactions of nanomedicine in manyphysiological processes play significant roles in their biologicalactivities and therapeutic outcomes in living systems, includinghow to escape undesired phagocytosis and clearance by thehost immune system and how to localize at the targetedpathological regions without side effects.39−41 In line with thesefactors, the erythrocytes, commonly known as red blood cells(RBCs), may act as a valuable model for nanomedicine toexplore and mimic their specific properties in vivo.42−44

Normally, RBCs are capable of serving as oxygen carriersthroughout the body with prolonged circulation time (∼120days) in the vascular system.45 Moreover, the RBCs can easilyescape the phagocytic immune cell-controlled clearance anddegradation through the expression of several biomarkers onthe cell membrane including “don’t eat me” marker CD47 andsignal-regulatory protein α (SIRPα) receptors.46 Such remark-able properties of RBCs suggest a promising strategy allowingtraditional nanoparticles to achieve long circulation time andspecific membrane functions for potential utilization in livinganimals.47,48 For example, RBCs-mimicking nanoparticles havebeen designed by Zhang’s group for the development of novelbiomimetic and long-circulating nanoplatforms based on theirgreat biocompatibility and limited immunogenicity.49 Theyprovided a smart strategy to fabricate RBCs membrane-camouflaged nanoparticles (RBCs-NPs) in two steps: RBCsmembrane vesicle extrusion and vesicle−nanoparticle fusion(Figure 2a). Briefly, the isolated RBCs from whole bloodunderwent membrane rupture using hypotonic treatment toremove their intracellular components, and the emptied RBCswere washed and extruded through porous membranes tocreate erythrocyte-derived vesicles. The final core−shellstructure of RBCs-NPs was achieved by fusing the RBCvesicles with carboxyl-terminated PLGA nanoparticles viamechanical extrusion.50 Moreover, similar levels of proteincontent and expression of CD47 were demonstrated on RBC-NPs compared with native erythrocytes, and superiorcirculation half-life (39.6 h) was also achieved for RBC-NPsthan that in conventional polyethylene glycol (PEG) modifiednanoparticles (15.8 h) in mice. These results strongly indicatedthat RBCs-NPs could effectively prolong the circulation time inblood and mimic the specific membrane functions in livingconditions.Furthermore, toward the biomedical applications of eryth-

rocyte-derived nanoparticles, excellent selectivity is anotherdesirable feature that promises minimization of off-target sideeffects for effective disease diagnosis and therapeutics.51 So far,various chemical functionalization methods have beenemployed to modify nanoparticles with targeting ligands fortheir specific binding with overexpressed antigens (e.g.,carbohydrates, proteins, etc.) on the cell membranes at diseasedsites.52−54 In order to nondisruptively integrate targetingligands on the surface of RBCs-NPs, a lipid insertion strategy,which tethers targeting ligands to lipid molecules for RBCmembrane insertion, was recently developed based on theintrinsic fluidity and dynamic conformation of the phospholipidbilayer of cell membrane (Figure 2b).55 This approach couldnot only allow for the membrane functionalization of varioustargeting ligands at different molecular weights from small-molecule folate (441 Da) to macromolecule nucleolin-targetingaptamer AS1411 (9000 Da), but also achieve the adjustabilityof ligand density by controlling the lipid-tethered ligand input,

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

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DOI: 10.1021/acs.bioconjchem.8b00103Bioconjugate Chem. 2018, 29, 838−851

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which holds great promise to improve the selectivity ofbiomimetic nanoplatforms with reduced off-target side effects.Encouraged by these promising pioneer studies, similar RBC-

membrane-derived approaches have been applied in manyother nanostructures including polymer nanoparticles,56

AuNPs,57 mesoporous silica nanoparticles,44 upconversionnanocrystals,58 and magnetic nanomaterials.59 All these RBCs-NPs hold unique capabilities to evade macrophage uptake andavoid immune clearance in living systems. Interestingly, bytaking advantage of their specific membrane−antigen inter-action, RBCs-NPs have recently been employed as abiomimetic nanosponge to clear poisonous pathologicalantibodies and toxins in vivo.60−62 For instance, Zhang et al.demonstrated that RBCs-NPs could act as nanosponges toarrest membrane damaging staphylococcal alpha-hemolysin (α-toxin) in the bloodstream and to divert them away from theircellular targets.60 In a mouse model, the nanosponges couldprevent toxin-mediated hemolysis and reduce their toxicity byneutralization, which exhibited remarkable improvement insurvival rate of toxin-challenged mice (Figure 2c). Similarly,Zhang et al. also reported that the RBCs-NPs could abrogatethe effect of pathological antibody-induced anemia disease inwhich the immune system produces autoantibodies to attracthealthy erythrocytes.61 Different from the conventionalimmune suppression drugs, the RBCs-NPs could serve as analternative target for pathological antibodies to protect healthyerythrocytes from macrophage phagocytosis (Figure 2d). Theseinnovative studies clearly demonstrated that erythrocytemembrane-derived nanoparticles represented promising ther-apeutic nanoplatforms for the broad range of biomedicalapplications on the basis of their multifaceted interactions withinnate immune system in living animals.

2. LEUKOCYTE-DERIVED NANOPLATFORMS

Leukocytes, also known as white blood cells, are inherent cellsin the immune system that protect the living body against bothinfectious diseases and foreign invaders.63,64 When the bodytissues are damaged by infection or injury with inflammatoryresponse generation, leukocytes are recruited from thebloodstream to the inflammation sites to effectively kill thepathogens and remove them by phagocytosis.65,66 During thisphysiological process, the specific surface interactions betweenleukocytes and endothelia play crucial roles in the recruitmentof immune cells at the targeted disease regions, owing to theoverexpression of endothelial adhesion molecules (e.g.,integrins) to selectively bind with ligands expressed onleukocyte surfaces (such as selectins).67−69 Therefore, inorder to mimic the membrane functions of leukocytes, avariety of bioinspired nanoplatforms have been constructed toexplore the underlying mechanisms of leukocyte−endothelialinteractions during the inflammatory response.25,70−73 Basically,the initial investigations to endow nanoparticles with theintrinsic features of leukocytes mainly rely on the surfacefunctionalization with target ligands.72,74 For example, bymodification of the polymersome nanoparticle surface withspecific leukocytal carbohydrate ligands (sialyl Lewisx),Hammer et al. demonstrated that this promising leuko-polymersome could firmly adhere to cell surfaces coated withthe inflammatory adhesion molecules including P-selectin andactivated β2-integrin (LFA-1, Mac-1, ICAM-1),74 whichindicated significant effects to the kinetic and mechanicalproperties 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 highlydemanding to reproduce the integrality and complexity of theleukocyte membrane.75,76 In recent years, researchers haveconsidered the possibility of efficient manipulation of the

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 byneutralizing antibodies (right). (Reprinted with permission from refs 49, 55, 60, and 61. Copyright 2011 and 2014 American Chemical Society, 2013Nature Publishing Group, and 2012 Royal Society of Chemistry.)



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integrated leukocyte membrane to enable the transfer of severalsignificant 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 ananoporous silicon (NPS) platform as hybrid leukocyte-likevectors (LLVs), which possessed specific leukocyte propertiesincluding biomarkers (CD45 and CD3z) and antigens (LFA-1or CD11a) on the vector surface (Figure 3a).77 Importantly,the promising LLVs have the potential to recognize andcommunicate with endothelial cells through receptor−ligandinteractions in an active and nondestructive manner (Figure3b), which could effectively improve the accumulation in tumorregions for further cancer therapy. Moreover, Zhang et al.demonstrated that grapefruit-derived nanovectors (GNV)coated with activated leukocyte membranes (IGNVs) couldsignificantly enhance their endothelial cell transmigrationcapability at inflammatory sites, and further effectively inhibittumor growth after encapsulation of doxorubicin (Dox) inIGNVs (Figure 3c).78 Intestinally, the targeted homingproperties of IGNVs toward inflammatory tumor tissuescould be blocked by some chemokine receptors includingLFA-1 and CXCR2, indicating that these receptors play keyroles in the recruitment and migration of leukocytes intoinflamed regions. These relevant studies demonstrated thatleukocyte-derived nanoparticles supply a versatile technique to

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

3. PLATELET-DERIVED NANOPLATFORMS

As circulating sentinels in the bloodstream, platelets (alsoknown as thrombocytes) are key components in hemostasisand thrombosis during blood vessel injuries, and also performsignificant functions in the development of lymphaticvasculature and mediation of innate or adaptive immuneresponse.79−81 Moreover, platelets are involved in thepathological processes of multiple health issues includingcancer, inflammation, and infection, acting in a key role tomediate the platelet−cell interactions and their behaviors.82−84

However, extensive understanding of the detailed mechanismsand significant roles of platelets in these pathophysiologicalprocesses remain under unclear.85 Fortunately, recent studieshave demonstrated the outstanding merits of platelet-mimicking nanoparticles for the exploration of variouspathological pathways, including phagocytotic escape, immunesystem activation, and selective adhesion to damagedvasculature and tumor tissues.86,87 Until now, severalapproaches have been adopted to integrate platelets withvarious types of nanoparticles for the purpose of developmentof platelet-mimicking nanoplatforms. One initial strategy is totransfer platelet-derived surface moieties (e.g., proteins, glycans,etc.) with specific functions to synthetic liposome nanoparticles(plateletsomes). For example, by modifying the liposomebilayer moieties which contain over 15 kinds of platelet

Figure 3. Schematic illustration of leukocyte-derived nanoparticles. (a) LLV structure and possible interactions between the functional groups onNPS 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 CancerResearch.)



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membrane glycoproteins, such as GPIb, GPIIb-IIIa, and GPIV/III, Renzulli et al. reported a smart plateletsome with greathemostatic 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 ofreceptors on the surfaces of platelets for targeting liposomedelivery, 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 arecapable of directing liposomes to receptors expressed onpathologically stimulated vascular territories.89

Despite the expected results in hemostasis and targetedpayload delivery presented by artificial plateletsomes, it is still achallenging task to replicate the flexible shape and highlycomplex platelet−cell interactions.90−92 In order to fullypreserve the integrality of platelets, recent studies haveindicated the development of biomimetic nanoparticles thatcombined the plasma membrane of platelets with variousfunctional nanostructures. For instance, Zhang et al. developeda smart strategy utilizing platelet membrane-cloaked PLGA

nanoparticles (PNPs) for the specific clearance of antiplateletantibodies in blood for effective treatment of immunethrombocytopenia (Figure 4a).93 The PNPs could act asdecoys to strongly bind with pathological antiplatelet antibodiesand subsequently neutralize them with considerable therapeuticefficacy for immune thrombocytopenia purpura in a murinemodel. Furthermore, they also reported the PNPs which endowthe nanoplatform surface with platelets for the adherence ofseveral disease-relevant substrates (Figure 4b).94 The resultingPNPs 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 indamaged vasculature of living animals. Moreover, enhancedtherapeutic efficiency was determined to inhibit the growth ofneointima in a coronary restenosis rat model by loading withdocetaxel (Dtxl) and vancomycin (Van), which presented amultifaceted approach in developing an effective nanoplatformfor disease-targeting treatment. Such unique approaches basedon platelet-derived nanoplatforms provided promising feasi-

Figure 4. Platelet-derived nanoplatforms. (a) Scheme of PNP preparation and activation as decoys to neutralize pathological antiplatelet antibodiesfor the treatment of immune thrombocytopenia. (b) (Left) H&E-stained arterial cross sections of normal (top) and zoomed-in (bottom) tissues in arat 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 93and 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 tumorcells. (Reproduced with permission from refs 106 and 113. Copyright 2011 Nature Publishing Group and 2017 John Wiley & Sons).



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bility to fabricate the investigations of platelet−cell interactionsin complicated pathophysiological processes including hemo-stasis, inflammation, and infection in living conditions.

4. EXOSOME-DERIVED NANOPLATFORMS

Exosomes, one type of intrinsic cell-derived small membranevesicle usually with diameter range of 40−100 nm, can besecreted by most cell types in biological fluids.95,96 Typically,the surfaces of exosomes consist of different kinds of biologicalcomponents, such as chaperone proteins, adhesion molecules,and metabolic enzymes,97,98 which exert their biological effectsin a highly diversified manner, including activation of targetedcell surface receptors via protein−ligand interactions, mergingof the membrane contents with the recipient cell membrane, ordirect delivery of proteins, mRNA, and lipid into recipientcells.99−101 Most of these features are determined by theirspecific surface protein expression originating from parentcells.102,103 Therefore, exosomes have been well recognized asan attractive nanoplatform for extensive biomedical applicationsdue to their versatile and alterable membrane functions.104−107

For example, Wood et al. recently produced dendritic cell-derived exosomes for targeted delivery of short interfering RNA(siRNA) into the mouse brain for Alzheimer’s diseasetreatment (Figure 5a).106 In order to reduce the immunoge-nicity and achieve a targeting effect, the dendritic cells wereengineered to produce natural exosomes with membraneprotein (Lamp2b) expression for selective fusion withneuron-specific RVG peptide. Upon loading exogenoussiRNA through electroporation, the RVG-targeted exosomescould effectively deliver GAPDH siRNA to neurons, microglia,and oligodendrocytes in the mouse brain after intravenousinjection. Moreover, efficient mRNA (∼60%) and protein(∼62%) knockdown of a therapeutic target in Alzheimer’sdisease (BACE1) was determined in vivo, which clearlydemonstrated the effective therapeutic effects mediated bysiRNA delivery nanoplatform with modification of exosome.

Furthermore, Kang et al. also prepared dual-functionalexosome-based drug delivery vehicles based on superparamag-netic nanoparticle clusters for effective tumor treatment.107

With a strong superparamagnetic property under an externalmagnetic field, the drug-loaded exosomes could be efficientlyaccumulated at desired tumor regions for significant inhibitionof tumor growth in living animals. This strategy endowed theexosomes with magnetism and could thus advance the potentialusage of exosomes in vivo.In spite of the promising perspectives of exosomes in

biological sciences, so far, how to rapidly produce, isolate, andpurify exosomes in sufficient amounts remains a technicalchallenge that requires more research effort.108,109 Moreover,natural exosomes usually have complicated surface compo-nents, which may raise potential concerns to interfere with theexosome−cell interactions during long-distance intercellularcommunication and targeted payload delivery.110,111 To addressthese issues, synthetic exosome-like nanoparticles, whichcombine desired membrane proteins with phospholipid bilayeron the surface of artificial exosomes, have been developed inrecent years.112−115 For instance, by utilizing biomimeticsynthesis strategies, Liu et al. presented biofunctionalizedliposome-like nanovesicles (BLNs) that are capable ofartificially encapsulating two different kinds of tumor targetingmoieties for effective drug delivery and cancer therapy in livingmice (Figure 5b).113 Upon genetic engineering with humanepidermal growth factor (hEGF) or anti-HER2 affibody astargeting ligands, the BLNs exhibited higher biological activityand selectivity toward EGF receptor-overexpressing cancercells, and enhanced therapeutic outcomes than clinicallyapproved liposomal-Dox in HER2-overexpressing BT474tumor xenograft models. In addition, Gho et al. also reportedexosome-mimetic nanovesicles with anticancer drug loading fortargeted delivery in chemotherapy of cancer.114 The hybridnanovesicles were prepared through breakdown of monocytesor macrophages by utilizing a serial extrusion with filters of

Figure 6. Schematic illustration of bacterial-mimicking nanoplatforms. (a) Modulation of antibacterial vaccines via BM-AuNPs. (b) TEM image andstability of BM-AuNPs (top); CD11c+ and INF-γ expressions from activated dendritic cells and T cells in vivo (bottom). (c) EGFPDNV productionfrom EGF expressing bacteria. (Reproduced with permission from refs 130 and 133. Copyright 2016 American Chemical Society and 2017 Elsevier.)



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different pore sizes. Interestingly, compared with traditionalexosomes, these nanovesicles presented 100-fold higherproduction yield and exhibited excellent targeting capabilityby mimicking the topology of membrane proteins. Moreover,enhanced cell death and tumor growth inhibition without toxicside effects have also been identified in living mice, clearlysuggesting that the bioengineered nanovesicles could serve asnovel exosome-mimetics with selective tumor affinity forenhanced treatment. These simplified exosome nanostructuresnot only could be manufactured in a mass production mannerthrough standard technology in industry, but they also providedesired surface functionalization methods to achieve specificinvestigation of exosome−cell interactions in vitro and in vivo.

5. BACTERIAL-MIMICKING NANOPLATFORMSIt is well-known that there are a variety of microbes (e.g.,bacteria, viruses, fungi, and other tiny organisms) throughoutthe human body, which can definitely act as essentialcomponents of immunity and functional entities to influencefundamental metabolism and modulate cell host−microbeinteractions in living systems.116−118 As one type of importantmicrobes, bacterial species are actually of great practical interestto human beings, and they are essential for normal bodyfunctions including digestion and immune response. In general,a majority of bacteria are harmless owing to the protectiveeffects of the innate immune system; some are even particularlybeneficial in the gut.119,120 However, several kinds of extraneousbacteria are indeed pathogenic and induce various infectiousdiseases, including cholera, anthrax, tuberculosis, and syph-ilis.121−123 Normally, the diverse bacterial surface componentsplay critical roles in the pathogenesis of infectious disease sincethey mediate the specific activities of bacteria−cell interactionsin living conditions, including colonizing tissues, resistingphagocytosis, and activating immune responses.124,125 Withthese attractive features, the excellent bacterial-mimickingsystems that can avoid the pathogenicity of living bacteria aswell as preserve the integrality of bacterial membrane havebecome highly desirable in recent decades.126

Considering the promising ability of nanoparticles to mimicthe aforementioned key aspects of the cellular membrane,various bacteria-mimicking nanoparticles have been proposedin recent years for biomedical applications including thedevelopment of antibacterial vaccines and targeted deliveryvehicles.127−131 For instance, by using Escherichia coli as amodel pathogen, Zhang et al. developed a unique bacterialmembrane-cloaked gold nanoparticle (BM-AuNPs) as anexciting and robust antibacterial vaccine (Figure 6a).130 Thebacterial outer membrane vesicles (OMVs) were collected andfurther coated on the surface of small AuNPs (∼30 nm). Aftersubcutaneous injection, the BM-AuNPs induced rapidactivation and maturation of dendritic cells in lymph nodes ofvaccinated mice. Interestingly, the BM-AuNPs presented ahigher efficacy to elicit bacterium-specific B-cell and T-cellresponses in the vaccinated animals than those elicited byOMVs only, indicating that the synergistic action of bacterialmembranes and AuNP cores could benefit each other forenhanced immune responses (Figure 6b). These results clearlyshowed that the synthetic nanoparticles with natural bacterialmembrane modification hold great promise for fabricatingeffective antibacterial vaccines.Moreover, so far, the bacterial-mimicking strategy has also

been applied to establish the effective delivery vehicles towardenhanced targeting of diseases regions.132−135 For instance,

Gho et al. engineered one novel nanovesicle system by utilizingbacterial protoplast (a type of cells with wall structureremoved) as a unique cargo for targeted delivery (Figure6c).133 After removing the toxins in the outer wall of thebacteria, the bacterial protoplast-derived nanovesicles (PDNV)could be fabricated by serial extrusions on the basis ofnanosized membrane filters. The PDNV could selectivelydeliver chemotherapeutics (e.g., Dox) to tumor tissues viareceptor-mediated interactions through the specific surfaceexpression of tumor-targeting moieties, such as epidermalgrowth factor (EGF), etc., in in vivo experiments furtherindicated that the drug-loaded PDNV could not only efficientlyinhibit the tumor growth, but also reduce the chemo-therapeutics-induced adverse effects in the heart after systemicadministration to mice. These innovative studies demonstratedthat bacterial-mimicking nanomaterials provide great potentialto systematically understand the complicated bacteria−cellinteractions during the treatment of diverse infectious diseases.

6. VIRUS-MIMICKING NANOPLATFORMSAs a small infectious species, virus can replicate itself only whenit invades into the host including animals, plants, bacteria, andother organisms.136,137 Naturally pathogenic viruses possess theintrinsic ability to avoid immune system recognition and injecttheir 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 eventuallyresult in the death of the host.138−140 During the invasionprocesses, the outer membrane of the virus such as the capsid(a protein coat) or envelope (lipid bilayer) plays a significantrole in viral infection, including cell attachment and entry, generelease, and assembling of newly formed viruses.141−143

Therefore, the detailed understanding of the intricate virus−cell interactions will ultimately provide more information forthe design of innovative and effective therapeutics against viralinfection.So far, various viral vectors such as adenoviruses, retroviruses,

and lentiviruses, etc., have been utilized for successful clinicalapplications in the treatment of adenosine deaminase deficiencyand X-linked severe combined immunodeficiency.144−146

However, considering the case in which these viral vectorsare pathogenic and can be derived from viruses in naturalinfection, substantial concerns still occur regarding theirpotential issues in safety and immunogenicity.147 In order toachieve the benefits of viruses while greatly minimizing thesepotential issues of introducing pathogenic genes, extensiveresearch efforts have been engaged to design an initialgeneration of virus-like nanoparticles (VNPs) and virosomes,which are self-assembled nanoparticles and could mimic thecapsid and envelope structures with incorporation of functionalsurface glycoproteins in real viruses.148−152 For example,Sainsbury et al. reported the recombinant of novel VNPsbased on the capsid assembled by bluetongue virus structuralproteins (VP3 and VP7) from plant leaves (Figure 7a).152 TheVNPs presented specific capability to bind with cell surfacereceptors (e.g., αvβ3/β5 integrins) by integrating with cyclicRGD peptide, which could act as an attractive vehicle foreffective payload delivery including therapeutic drugs, contrastagents, proteins, and siRNA toward cancer treatment.Encouraged by these successful investigations, scientists

developed novel nanoparticles that mimic various naturalfeatures of viruses (e.g., surface antigens recognition,cytoplasmic capsid assembly, immune system escape, etc) to



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explore the virus-cell interactions through the specific surfacemodifications of these assembled carriers.153−155 For example,inspired by viral capsid protein structures, Ni and Chau recentlyconstructed a biomimetic capsid assembled by syntheticpeptide with specific nanoribbon and nanococoon shapes andstriped surface patterns (Figure 7b).153 The rational design ofthis smart peptide contained different segments for DNAbinding and β-sheet assembly, which offered the capabilities ofartificial capsid with excellent stability, low permeability, andresistance to enzyme digestion for gene protection. Moreimportantly, this biomimetic strategy could regulate and controlthe properties of synthetic capsid by introducing diversefunctional groups into assembling blocks, which thereforeproduced a feasible model to understand the peptide/DNAinteraction during the capsid encapsulation process. Thesepromising studies suggested that virus-mimicking nanoparticlescould provide more beneficial information for effectivepharmaceutical development against viral infection and detailedunderstanding of virus activities in living animals.

■ CONCLUSION AND PERSPECTIVESCurrently, extensive nanomedicine holds great potential for theprecise diagnosis and effective therapeutics of various humandiseases in clinical practice. However, a detailed understanding

regarding how nanomedicine interact with the intricateenvironment in complex living systems, still remains challeng-ing. To this end, inspired by the diversified membranestructures and functions of natural prototypes, relevant researchhas increased exponentially for the development of membrane-mimicking nanoplatforms, which endow the abiotic nanoma-terials with specific biological functionalities to investigate thecomplicated interactions and activities of nanomedicine inhuman bodies. In this review, we focused on the strategiesestablished recently for the development of membrane-cloakednanoplatforms derived from inherent host cells (e.g.,erythrocytes, leukocytes, platelets, and exosomes) and invasivepathogens (e.g., bacteria and viruses), mainly attributed to theirversatile membrane properties in biological fluids. Therepresentative examples of different kinds of biomimeticmembrane-cloaked nanoplatforms in living system aresummarized in Table 1. Despite the wide exploitation ofdiverse membrane-mimicking strategies in recent decades, thereis still a long way toward conducting any clinical trials in thisresearch field.For example, these “cloaking” strategies could effectively

endow various nanoparticles with specific advantages of diversebiological membranes, such as long circulation time in blood(erythrocytes), great selectivity at inflamed endothelial regions(leukocytes), and excellent capacity to evade immune systemrecognition (viruses). However, numerous works are greatlyexpected to formulate these bioinpired nanoplatforms byavoiding their undesirable shortcomings, including complexsynthetic and purification routes (platelets), lack of stand-ardized protocol for preparation and isolation in sufficientamounts (erythrocytes and exosomes), and potential concernsregarding safety and immunogenicity in the human body(bacteria and viruses) (Table 2). Therefore, great challengesstill remain in this research area which require extensiveexploitation in the near future. First of all, although thesebiomimetic strategies based on various cell membranes andpathogens have been widely established in recent years, it is stilldifficult to maintain the integrality and functionality of naturalentities due to the requirement of multiple labor-intensiveprocesses during the fabrication of these membrane-mimickingnanoparticles, such as genetic engineering or prolonged ex vivohypotonic treatment.49,149 For example, the surface integralityof RBCs could be compromised during ex vivo producing ofRBC-coated nanoparticles, which may result in decreasingcirculation time and rapid clearance by the immune system.8,76

Therefore, researchers should pay more attention to optimizingthe membrane extraction techniques and particle−membranefusion procedures, which will minimize the structuralalterations for more accurate investigations of the relationshipsbetween the interfaces of nanotechnology and biology.Furthermore, even though several rational designs of

membrane-cloaked nanoplatforms are inspired by naturalbiomoieties including living cells and pathogens, the potentialimmunogenicity of these biomimetic nanostructures may stilloccur as undesired side effects and safety concerns, especiallyfor pathogen-mimicking nanoparticles.162 For example, a seriesof conformational changes of the membrane-anchored frag-ments (e.g., proteins, glycans, etc.) might be occurring duringthe period of membrane extraction or fusion with nanoparticles,which could be recognized as invaders to activate immuneresponse.163 Significantly, it is worth noting that some certaindegrees of immunogenicity could be beneficial to human healthwhen 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) assembledby virus proteins (VP3 and VP7). Scale bar: 200 nm. (b) Chemicalstructure of peptide and TEM images of self-assembled capsid withnanoribbon and nanococoon structures in the absence and presence ofDNA as templates. Scale bar: 100 nm. (Reproduced with permissionfrom refs 152 and 153. Copyright 2014 and 2017 American ChemicalSociety.)



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vaccines to stimulate the adaptive immune responses. However,the potentially immunogenic components of pathogens thatmay induce unexpected immune response/reaction in vivomust be removed or inactivated, and their biosafety should bethoroughly addressed by the examinations in preclinicalstudies.164

In summary, the biomimetic membrane-cloaked nanoplat-forms, by integrating the diversified properties of variousbiological membranes and nanomaterials, provide a brightperspective for the investigations regarding the performance ofnanomedicine within the intricate environment during diversephysiological and pathological processes in living systems.

Along with all the innovative studies in these research areas, webelieve that these bioinspired strategies conjugated withattractive features of nanomaterials will promote the develop-ment of efficient and precise nanomedicine and finally have apromising outlook to benefit human health.

■ AUTHOR INFORMATIONCorresponding Author*E-mail: [email protected] Lin: 0000-0001-9572-2134Bengang Xing: 0000-0002-8391-1234

Table 1. Representative Examples of Biomimetic Membrane-Cloaked Nanoplatforms in Living Systems

membranesources corea size (nm) payloadb

loadingcapacity

targetingmoietiesc

circulation time (t1/2,h) %ID/g in organsd (24 h) ref

Erythrocytes PLGA 80 −− −− −− 39.6 L: 39, S: 26, 49G: 14, B: 10

MSNs 108 Ce6 21% −− 11.5 L: 40, S: 13, 41Dox 39% G: 15, T: 18

Bismuth (Bi) NPs 56 Bi 70% FA 17.1 L: 34, S: 19, 156K: 7, T: 9

Leukocytes GNV 200 Dox 75% CXCR2 LFA-1 −− L: 18, S: 14, 78K: 7, G: 8, T: 7

−− 120 PTX 76% LFA-1 CD45 −− L: 48, B: 12, 157K: 13, T: 7

liposome 115 DM1 96% α4β1- integrin 4.9 L: 62, G: 21, 158K: 9, S: 6

Platelets PLGA 113 Dtxl 2.1% surface- glycans 33.2 L: 42, S: 28, 94200 Van 4.0% K: 4, D: 17

nanogel 121 Dox −− TRAIL, 32.6 L: 19, S: 5, K: 159P-selectin 12, G: 7, T: 53

Exosomes −− 88 siRNA 25% Lamp2b −− L: 19, S: 16, 106M: 18, H:17

−− 105 ICG >70% hEGF 7.2 −− 113Dox anti-HER2

Bacteria −− 42 Dox 40% hEGF −− L: 7, S: 14, K: 1336, G: 6, T: 62

−− 90−133 siRNA 15% anti-HER2 −− −− 160Viruses −− 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: 37aMSNs: 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

membranetypes advantages disadvantages

Erythrocytes Long circulation time in blood Time-consuming purification methodsSimple approaches for membrane functionalization Lack of standardized protocol for preparation, purification, and storage in

sufficient amountsLeukocytes Great selectivity at specific disease regions and regulation of

inflammatory responseInadequacy reproducing the integrality and complexity of leukocytemembrane

Platelets Favorable properties in treating hemostasis, hemorrhage andtargeted payloads delivery

Complex synthetic and purification routesLimited assessment of immunogenic potential

Exosomes Promising candidate for payload delivery Lack of standardized methods to rapidly produce, isolate, and purify exosomesin sufficient amountsLong-distance cell-to-cell communications

Bacteria Great antibacterial vaccines and targeted delivery vehicles Potential concerns regarding safety and immunogenicityViruses Excellent capacity in cellular targeting, entry, and avoiding immune

system recognitionPotential concerns regarding safety and immunogenicity



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NotesThe authors declare no competing financial interest.

■ ACKNOWLEDGMENTSThe authors acknowledge the financial support by NTU-AIT-MUV NAM/16001, RG110/16 (S), Merlion 2017 Program(M4082162), JSPS-NTU Joint Research (M4082175) and (RG35/15) awarded in Nanyang Technological University,Singapore, and National Natural Science Foundation ofChina (NSFC) (No. 51628201).

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http://dx.doi.org/10.3791/56416

http://dx.doi.org/10.3791/56416


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