key: cord-0682047-om1wbn59
authors: Pereira-Silva, Miguel; Chauhan, Gaurav; Shin, Matthew D.; Hoskins, Clare; Madou, Marc J.; Martinez-Chapa, Sergio O.; Steinmetz, Nicole F.; Veiga, Francisco; Paiva-Santos, Ana Cláudia
title: Unleashing the potential of cell membrane-based nanoparticles for COVID-19 treatment and vaccination
date: 2021-06-06
journal: Expert opinion on drug delivery
DOI: 10.1080/17425247.2021.1922387
sha: a77296e6d8c01d9e92981d02774528f621d169b0
doc_id: 682047
cord_uid: om1wbn59

Introduction: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a particular coronavirus strain responsible for the coronavirus disease 2019 (COVID-19), accounting for more than 3.1 million deaths worldwide. Several health-related strategies have been successfully developed to contain the rapidly-spreading virus across the globe, toward reduction of both disease burden and infection rates. Particularly, attention has been focused on either the development of novel drugs and vaccines, or by adapting already-existing drugs for COVID-19 treatment, mobilizing huge efforts to block disease progression and to overcome the shortage of effective measures available at this point. Areas covered: This perspective covers the breakthrough of multifunctional biomimetic cell membrane-based nanoparticles as next-generation nanosystems for cutting-edge COVID-19 therapeutics and vaccination, specifically cell membrane-derived nanovesicles and cell membrane-coated nanoparticles, both tailorable cell membrane-based nanosystems enriched with the surface repertoire of native cell membranes, toward maximized biointerfacing, immune evasion, cell targeting and cell-mimicking properties. Expert opinion: Nano-based approaches have received widespread interest regarding enhanced antigen delivery, prolonged blood circulation half-life and controlled release of drugs. Cell membrane-based nanoparticles comprise interesting antiviral multifunctional nanoplatforms for blocking SARS-CoV-2 binding to host cells, reducing inflammation through cytokine neutralization and improving drug delivery toward COVID-19 treatment.

Severe acute respiratory syndrome-related corona-virus (SARS-CoV-2) is the novel virus termed as the causative agent of the COVID-19 disease outbreaks [1, 2] . More than 150 million cases are reported as of April 30, 2021, with above 3.1 million deaths across the globe. The pandemic is still expanding, and the challenges are still increasing with the emergence of new waves in many countries [3] [4] [5] . This difficult situation demands the deployment of all possible management options available. The biggest challenge of 2021 and beyond is to develop effective therapeutic or vaccine candidates. Several options, including nanotechnology tools, are on the table and being explored to counter the pathology associated with this virus [6] . The role of nanomedicine (i.e. usage of nanotechnology for medical applications) against nanosized viruses (80-160 nm) is crucial, and nano-based approaches have attracted special attention for developing versatile nano-based diagnostics, therapeutics, and vaccines to tackle COVID-19 as reviewed elsewhere [7] [8] [9] [10] [11] [12] [13] [14] [15] . A typical nanomedicine strategy is to develop nanocarriers -such as nanoparticles -to increase the efficacy of newly designed or repurposed therapeutic molecules, including antivirals, small molecules, as well as antigens [6, 16, 17] . Also recently, biomimetic strategies including antigen or nucleic acid vaccination have shown interesting results and emerged as strong contenders for a universal COVID-19 vaccine, achieving particular success the recentlyapproved messenger RNA-encapsulating lipid nanoparticles [6, 18] . However, additional strategies are also sought after as those may bring novel insights in how to counteract the pandemic. One of these strategies involve the use of nanoengineered biomimetic systems either armed with or mimicking the biofunctionality of cellular components -which endow them with the capability of replicating and modulating cellular processes and biological cues -still underexplored for COVID-19 applications. Particularly, the incorporation of such bioderived or bioinspired components can be achieved by unleashing the potential of cell membranes as complex, fullyreplicable and multivalent biological components for (1) coating nanoparticle cores, by assembling cutting-edge cell membrane-coated nanoparticles; or by (2) functioning as cell membrane-derived nanovesicles devoid of nanoparticle core, known as cell membrane nanovesicles. These cell membranebased nanoparticles are a relatively new class of materials merging distinct cell membrane biofunctionalities with the versatility of nanoparticles, creating thus far innovative nanoplatforms showing a vast array of applications within the biomedical field. The purpose of a cell membrane-derived surface is to act as a biological cloak encasing the interior contents, protecting them from premature clearance, degradation or release, and acting as a multi-addressable, multivalent and tailorable interface to mimic and boost biological interactions. Cell membrane-based nanoparticles are already showing some exciting results in COVID-19 management [19] [20] [21] . In this review, the authors will comment on the recent advances and future prospects of cell membrane-based nanoparticles for harnessing COVID-19, focusing on the potentialities of recently developed cell membrane-coated and cell membrane nanovesicle-based COVID-19 therapies and providing a roadmap of possible future applications of this technology for COVID-19 management. Additionally, the review will build on previously reported biomedical advances regarding cell membrane bioengineering and surface functionalization toward full unleashing of the potential of cell membranebased nanoparticles for multifunctional, biomimetic and innovative COVID-19 therapeutics and vaccination.

SARS-CoV-2 is a positive-sense enveloped RNA virus with a single stranded RNA genome of approximately 34 kilobases and a nucleocapsid of helical symmetry [22] . This 80-160 nmsized virus presents a roughly spherical or moderately pleiomorphic morphology, with a condensed mass of nucleic acid and nucleocapsid protein underneath a well-defined lipid bilayer envelope (Figure 1 ). The S protein (spike glycoprotein) enables the attachment of the viral particle to host cells and membrane fusion, hence promoting the entry of SARS-CoV-2 into the host cells [23] [24] [25] [26] [27] [28] [29] . The angiotensin-converting enzyme 2 (ACE2) is the key receptor for entry of SARS-CoV-2 into the host cells. Cellular proteases (human airway trypsinlike protease (HAT), cathepsins and transmembrane protease serine 2 (TMPRSS2)) control the viral entry process by splitting the spike protein and initiating further penetration mechanisms [30] .

The interaction between the ACE2 and SARS-CoV-2 is facilitated by polar interactions [31] [32] [33] . Some of the major therapeutic targets identified include interaction sites of viral S protein with ACE2, TMPRSS2, viral proteases (3CLpro and PLpro) and RNA polymerase (RdRp) [34] [35] [36] [37] [38] [39] [40] . Structures involved in SARS-CoV-2 binding (either for infection via ACE2 or neutralization via convalescent serum antibody) were solved at unprecedented speed, and such evidence accelerates both vaccine and therapeutic developments. For example, in silico immunoinformatic studies leveraging SARS-CoV-2 homology to SARS-CoV provided a shortlist of candidates for vaccine epitope design even prior to downstream SARS-CoV-2 convalescent serum neutralization studies (reviewed in [41] ). The pathological framework of SARS-CoV-2 infection is not only limited to its transmission inside the host cell, as host's

• COVID-19 is an ongoing disease provoked by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); • Novel prophylactic and therapeutic measures are urgently needed for  COVID-19 management;  • Nanoparticles have been receiving particular attention for COVID-19 treatment and vaccination; • Cell membrane-based nanoparticles acanreproduce the surface repertoire and biofunctionality of native cell membranes; • Cell membrane nanovesicles and cell membrane-coated nanoparticles represent the two main classes of cell membrane-based nanoparticles; • Cell membrane-based nanoparticles are promising multifunctional nano-based approaches for multivalent COVID-19 treatment and vaccination.

This box summarizes key points contained in the article. immune system response against it is also very crucial. A dysfunctional immune response initiated after SARS-CoV-2 infection may also result in the worsening of the condition both locally as well as systemically [42] [43] [44] [45] . Active replication of the virus results in the release of damage-associated molecular patterns, which further triggers the localized flux of proinflammatory cytokines, chemokines and subsequently attract immune cells to the site of infection [46] [47] [48] . Excessive infiltration of immune cells results in the pro-inflammatory cytokine storm, provoking pulmonary edema, pneumonia, and severe lung damage. Multiple organs may also become severely affected by this widespread inflammation and antibodydependent enhancement (ADE) by non-neutralizing antibodies produced by B-cells [48] .

Current COVID-19 therapy mostly resort to the use of antivirals (to inhibit the multiplication of virus) and immune modulators (to manage the response of immune system to counter the virus). In the absence of an exclusive antiviral treatment against SARS-CoV-2 infection, its management is still a great challenge [6] . In parallel, the scientific community is using high-throughput drug discovery platforms to develop new small molecules, repurpose existing drugs and designing formulations for these candidates [49] [50] [51] [52] [53] [54] [55] . Input of nanotechnology becomes vital here to develop creative strategies to maximize the efficacy of currently available therapeutics.

Nanomedicine strategies can circumvent various disadvantages and potentiate the therapeutic benefits of repurposed antiviral molecules by increasing bioavailability, localizing the delivery to the infection sites (viral reservoir sites such as ACE 2 expressing cells, domains of viral S protein, cathepsinbinding sites), decreasing off-targeted effects, and weakening the resistance development mechanisms [56, 57] . Nanocarriers can deliver a range of small molecules, biologicals (RNA interference, antibodies, proteins, antigens), peptides, and combined therapeutics as well [6, [58] [59] [60] . Nanocarriers also ensure the physical prevention of the biological molecules against the premature degradation in harsh biological environments, whilst evading the immune recognition and minimizing renal and/or hepatic clearance [6, 61] . Sustained release of nanopar-ticle´s loaded compounds (e.g. antiviral molecules) can also prevent the viral rebound and improve the overall therapeutic management. In addition to payload and antigen delivery via nanocarriers, nano-based antiviral strategies with possible applications to harness COVID-19 include development of virucidal nanomaterials and harnessing 'nanodecoy' abilities of nanocarriers toward virus immobilization and cytokine neutralization [58] ( Figure 2 ). SARS-CoV-2 infection is evolving continuously and some of the viral mutants are escalating the healthcare challenges. COVID-19 vaccines are introduced as a parallel strategy to reduce the morbidity and mortality worldwide. Current COVID-19 vaccines are based on both replicating and non-replicating platforms. One of the biggest challenges associated with the development of COVID-19 vaccine is to assure its safety while maintaining efficacy in the global heterogeneous population [6, 41] . The input of nanotechnology in vaccine development is exciting the scientific world on many fronts. Various nanovaccines are under consideration to develop a safe and effective immune response against potential targets like the viral S protein [62, 63] . Along with the safe and effective delivery of the antigens, nanotechnology can assist a successful vaccine development by allowing a better control over antigenic release and display, cellular presentation and uptake, and targeting both adaptive (T cells, B cells) and innate (macrophages, monocytes, neutrophils) immune systems. For example, polymersomes, which are artificial polymer-based vesicles enclosing an aqueous core, were used to display at the surface spike protein receptor-binding domain (RBD) resulting in strong humoral neutralizing response to SARS-CoV-2 as well as robust cellular immunity [64] . Also in this context, nanomaterials possessing intrinsic adjuvant properties are of utmost importance to optimize the safety and efficacy parameters. These vaccine adjuvant nanocarriers can play a key role to design effective prophylaxis against SARS-CoV-2 infection [6, 18] . Once COVID-19 is associated with inflammatory stages characterized by cytokine overproduction and a so-called cytokine storm, strategies to neutralize inflammatory cytokine production and reduce inflammation recurring to nanotechnology are also receiving special attention [65] .

Apart from these conventional nanomedicine strategies, biomimetic nanosystems have emerged as an alternative option against such threatening pathogens. Advantages associated with these biomimetic nanosystems in terms of their surface functionalization, tailorability, biocompatibility, and reproducibility make them a versatile nanomedicine candidate. With optimized biophysiochemical properties, these nanosystems possess a great potential both for therapeutic and vaccine delivery [66] [67] [68] [69] [70] . Furthermore, the therapeutic or vaccine efficacy may also be benefited by their nature-inspired design and an intrinsic activity attributed to these biomimetic nanosystems.

The complexity of biological systems and the richness of the interactions established in biological environments have inspired the design of novel structures able to mimic the functionalities of biological components toward the maximization of biointerfacing and manipulation of biological cues [71] . This can be achieved for distinct strategies: through surface functionalization of nanocarriers with selective targeting ligands [72] ; by mimicking endogenous particles (e.g. lipoproteins [73] ) and vesicles (extracellular vesicles [74] ); by mimicking cell membranes natural structure, for example, recurring to synthetic constituents [75] ; or by coating nanocarriers with extracted cell membrane coatings from source cells [76] . Biomimetic nanocarriers display enhanced biocompatibility, biodegradability, specificity as well as minimal toxicity, and allow for improved immune response avoidance. Such bioinspired nanocarriers may also possess intrinsic activity to potentate the respective therapy or vaccine approach against infectious diseases. Such attributes have made biomimetic nanocarriers a very interesting approach toward enhanced delivery of therapeutics, as well as vaccines with applications in a wide range of diseases [77] .

Biomimetic nanotechnology approaches have been employed for SARS-CoV-2 vaccine design and therapy development, holding great promise, as these approaches operate on the same size scale as that of the pathogens [21] . For instance, mesenchymal stem cell-derived exosomes could be a valuable tool for reducing lung infection and alleviate COVID-19-related symptoms, in addition to posing as safe and fully-biocompatible nanovesicles toward targeted payload delivery to cells [78] . Besides the contemporary vaccines, i.e. inactivated and live-attenuated vaccines, the majority of vaccination approaches either under development, under clinical testing and already approved are based on novel biomimetic nanotechnologies, such as messenger RNA-laden lipid nanoparticles including approved Pfizer-BioNTech's BNT162b2 and Moderna's mRNA-1273, in which antigen-encoding messenger RNA is delivered into cells' cytoplasm and promote expression of a SARS-CoV-2 antigen, further displayed at the surface of host cells and enabling recognition by immune cells and immune response [79] [80] [81] ; lipid-based [82] and protein-based [83] nanoparticles exposing SARS-CoV-2 antigens; or adenoviral vectors encoding the SARS-CoV-2 spike protein [84] [85] [86] . Other approaches focus on subunit vaccines self-assembled into virus-like particles (VLPs) as reviewed in [41, 87] , bacteriabased expression of SARS-CoV-2 membrane and nucleocapsid proteins [88] . Given that the respiratory mucosa is the first main barrier for preventing SARS-CoV-2 invasion, another interesting strategy is to develop nanoparticles mimicking SARS-CoV-2 structure and activity to elicit anti-COVID-19 mucosal immunity in the respiratory tract ( Figure 3a ) [89] . Here, virosome-mimicking nano-enabled bionic vaccine was composed of synthetic double-stranded RNA poly(I:C) as immune adjuvant and simulating viral RNA, pulmonary surfactant-based liposomes mimicking viral capsid and SARS-CoV-2 receptor-binding domains (RBDs) acting as the viral spike, assembling a complex biomimetic inhalable nanovaccine sized around 154 nm (similar to SARS-CoV-2) and aimed at nasal administration (Figure 3 (b,c)). The nanovaccine was able to induce significative mucosal immunity through production of secretory immunoglobulin A (sIgA) by the respiratory mucosa, resulting in potent SARS-CoV-2 neutralization and blocking host cell invasion. Additionally, the nanovaccines could stimulate CD4+ T cells differentiation (Figure 3 (d-g)), thus promoting humoral activation and enhanced secretion of neutralizing antibodies, as well as B cell activation in the spleen (Figure 3 (h,i)). Importantly, the nanovaccine showed remarkable immune protection and mucosal immunity performance as compared to the groups subjected to intramuscular and intraperitoneal injection, including higher sIgA titers and duration of protection ( Figure 3 (j-m)) [89] .

While vaccines are undergoing clinical testing, there is an urgent need for therapeutics, especially as new waves of infection have already emerged globally. Moreover, nonvaccine therapeutics also may serve to benefit those whose immune systems approach senescence. Therapeutic intervention or even prophylaxis may come in the form of neutralizing antibodies [90] , however cold-chain requirements and risk for antibody-dependent enhance (ADE) of infection bear translational challenges [91] . Other SARS-CoV-2 spike protein binders in the development pipeline include ACE2inspired de novo design peptides [92, 93] and nanobodies (a single monomeric variable domain antibody) [94] . A particularly powerful decoy strategy is the multivalent presentation of such capture agents on a nanocarrier. This has been demonstrated recently using biomimetic virus-like particles (VLPs) with a multivalent sialic acid array to capture and neutralize influenza A-virus [68] . This biomimetic strategy can be easily adopted to SARS-CoV-2 treatment:a synthetic, highlybranched derivative of heparin was reported to improve antiviral activity against SARS-CoV-2 [95] . An alternative strategy to multivalent display is multi-expression. In this context, lipid nanoparticles containing mRNA encoding hACE2 led to decoy expression and SARS-CoV-2 neutralization [96] .

Inspired by the attributes of nanomaterials, of which nanoparticles have been explored the most, and the multivalent interactions performed by cells in a biological environment, cell membranebased nanoparticles have been receiving special attention to improve bio-interfacing and mimicking features of native nanocarriers.

Cell membranes can be extracted from distinct biological sources and (1) wrapped around nanocarrier cores by multiple possible combinations, resulting in cell membrane-coated nanoparticles, or (2) used as biomimetic cell membrane-derived nanovesicles composed of cell membrane-derived lipid bilayer surrounding an aqueous core. Considering the first case, the decorated nanoparticles have been adapted so far for distinct therapeutic destinations, according to the inherited and transferable functionalities conveyed by the surface repertoire of each cell membrane. Various cell membranes, such as red blood cells (RBCs), platelets, immune cells, cancer cells and bacterial membranes, have been reported [97] . Distinct cellular origins of cell membranes provide different array of biofunctionalities, namely (1) cancer cell membrane coatings for enhanced cancer therapies, owing to homotypic targeting of source cancer cells [98, 99] and immune system stimulation by collective surface antigens of the membranes [100] ; (2) RBC membrane coatings, for extended blood circulation profile, blood stability and immune escape, with applications in cancer therapy, acute liver failure [101] and diabetes management [102] ; (3) immune cell membrane coatings, for improved cancer biodistribution and accumulation, such as neutrophil membrane coatings, aimed at anti-inflammatory therapies, by acting as deep tissue penetrating decoys capable of neutralizing inflammatory mediators and alleviating rheumatoid arthritis [103] ; Leukocyte membrane coatings, for atherosclerosis treatment, to improve intimal foam cells targeting and migration properties [104] , or expanding interaction with damaged endothelium and surroundings by platelet membrane coatings [105] (Figure 4 ).

Altogether, these results have shown the versatility of cell membrane-coated nanoparticles, building on the multifunctional cell membrane shells and the diversity of the nanoparticle cores carrying active molecules, which have evidenced hitherto improved performance in treating several diseases. The composition of cell membranes can be enriched through functionalization with targeting ligands or antigens for maximized biofunctionality either via lipid-insertion methods in which the ligand is coupled to a lipid for intercalating into the lipid bilayer of cell membrane nanovesicles, or by cell engineering ( Figure 5 ) [106] .

So far, several classes of ligands from sugars ( Figure 5 ), aptamers ( Figure 5 ), peptides ( Figure 5 ), cell-penetrating moieties ( Figure 5 ), proteins (including enzymes and antibodies) ( Figure 5 ) and small molecular weight molecules ( Figure 5A ) have been actively explored for surface functionalization of cell membrane-based nanoparticles, including cell membranecoated ones [107] [108] [109] [110] [111] [112] [113] [114] (Table 1) .

Modulation of the lipid bilayer composition of the cell membrane nanovesicles can be achieved via hybrid approaches, either through (1) 9 ). In the first case, single cell membrane nanovesicles can fuse together under an extrusion process and combine the surface repertoire and inherent bifunctionalities of distinct cell membrane sources [119] . This strategy has been mainly used for cancer-targeted therapies so far. The second approach consists of intercalating native cell membrane-extracted proteins into the lipid bilayer of liposomes, through mixing lipidic building blocks with extracted protein content, as reported for leukocyte cell membrane-based biomimetic liposomes [120, 121] . A distinct study reported biomimetic liposomes based on RBC membrane vesicles functionalized with Escherichia coli (E. coli) membrane endotoxin-targeting polymyxin B (PMB)-lipid conjugates for concerted detoxification [122] . These RBC-based liposomes exhibited dual function, namely E. coli-anchoring abilities upon PMB binding to membrane endotoxins and exotoxinabsorbing abilities conferred by the lipid bilayer of RBC membrane nanovesicles, thus able to neutralize both endotoxin and exotoxin production, as in vivo studies showed. Lastly, fusion of exosomes -lipid bilayer nanovesicles secreted by almost all cells -with liposomes through freeze-thaw method assembling exosome-liposome hybrids has been reported, shedding light into advanced functionalization of cell membrane-derived nanovesicles [123] .

The highly problematic issues of antimicrobial resistance, emergence of new infectious diseases and the current COVID-19 pandemic have resulted in an urgent and vital need for new medical therapies and interventions to counteract this biological war we have found ourselves faced with. As stated before, nano-based therapeutic approaches are known to broadly leverage the performance of several conventional therapeutics by conferring protection to encapsulated active molecules from harsh in vivo environment, and improving pharmacokinetics [58] . This enables payload controlled release and long term therapeutic effect, as well as providing stimuliresponsiveness and tissue-targeting features toward maximized therapeutics [76, 124] .

Inspired by such advances, the potential of cell membrane coatings can be applied to harness infectious diseases such as COVID-19 and maximize therapeutic efficacy on account of the suitability of the nanoparticle cores and multifunctionality of the cell membrane coat to build advanced nano-based biomimetic platforms toward infection management, as discussed next. 

In infectious diseases, the range and complexity of pathological frameworks means they all progress via different routes and mechanisms. However, interaction at the interface between the host cell membrane and disease-specific pathogens always occurs, and hence this is an area of great interest in infection control. Cell membrane-coated nanoparticles have been shown to possess efficacy against bacterial and viral infections, above explored.

Recently, cell membrane-coated nanoparticles have been reported to counteract bacterial toxins due to the toxin's ability to adhere to cellular membranes and promote toxin neutralization and detoxification [125] . Particularly, RBC membrane-coated nanoparticles were effective in neutralizing the pore-forming toxin (PFT) staphylococcal alpha-hemolysin (αtoxin), acting as a toxin-absorbing nanosponge on account of the binding properties of PFT to their natural membrane substrates [126] . Further studies using nanodecoys coated with bacterial outer membranes of the pathogenic bacteria using H. pylori have been shown to act as anti-adhesion agents competitively binding at the mmembrane-bindingsites required for pathogen interaction and virulence [127] . In addition, cell membrane-coated nanoparticles can be loaded with antigens, toxoids or other immunostimulatory factors [124] , as biomimetic toxoid nanovaccines for effective vaccination strategies. These include α-hemolysin (Hla) detainment in RBC membranes wrapped around poly(lactic-co-glycolic acid) (PLGA) polymeric nanocores, showing superior immunoprotective properties in methicillin-resistant Staphylococcus aureus (MRSA) mice models of skin infection [128] ; multivalent nanotoxoids containing virulent proteins entrapped in RBC membrane-coated nanoparticles, effectively protecting against bacterial infection in vivo (Figure 6(a-c) ) [129] ; and PFTs-containing RBC membrane-coated nanotoxoids for immunization against PFT-producing bacteria [130] .

Gram-negative bacteria are known to produce outer membrane vesicles (OMVs), lipid bilayer-enclosed nanovesicles with enriched surface repertoire composed of bacterial antigenscapable of modulating host immune response; and adhesinsallowing binding to target cells, among other recognition molecules [131] . Studies have examined the use of these secreted vesicles as a form of cloaking mechanism. It is thought that exploitation of cell membrane-coated nanoparticles does not explicitly impact the immunomodulatory roles of the membrane proteins, but instead that the extracellular vesicles are enriched with membrane-associated proteins which hold a critical role in bacteria−host interaction [132] . By taking advantage of host cell-targeting and attachment abilities of OMVs, Helicobacter pylori-derived OMVs were coated onto PLGA NPs and competed with Helicobacter pylori for binding to the gastric epithelium ( Figure 6 (e)) [127] . The OMV membrane was able to maintain surface virulence factors and adhesins present on the bacterial membrane source. The OMV-coated NPs showed strong anti-adhesion properties evidenced by the reduced Helicobacter pylori binding to gastric cells.

Another report showed efficient internalization by Staphylococcus aureus -infected macrophages of nanoparticles loaded with triclosan-ciprofloxacin amphiphilic conjugates, further coated with macrophage cell membranes with intrinsic pathogen-targeting abilities [133] . This strategy is interesting because the establishment of secondary bacterial niches in macrophages may enable bacterial survival and result in therapeutic inefficiency. The macrophage cell membrane coating could improve the antimicrobial effect of the triclosan-ciprofloxacin conjugates and lead to efficient in vivo eradication of intracellular Staphylococcus aureus infection.

Recently, macrophage cell membrane-coated PLGA NPs showed affinity to virulence factors secreted by Pseudomonas aeruginosa as they were capable to capture, neutralize and display a variety of Pseudomonas aeruginosa antigens at the cell membrane's surface, inducing potent immune reaction ( Figure 6 (d)) [134] . These nanotoxoids could function as multiantigenic antivirulence nanoplatforms for potent immunization against bacterial infection. Additionally, macrophage membrane-coated magnetic composite nanoparticles were able to display antibacterial and anti-inflammatory properties by binding to bacteria and neutralization of toxins and inflammatory cytokines in bone infection [135] and sepsis [136] ( Figure 6 (f)).

Cell membrane-coated and cell membrane-based nanovesicles can act as nanodecoys able to trap and inactivate the pathogens of their infectious properties [67] . Several studies have explored their potential and have since demonstrated efficacy against diseases such as HIV (Figure 7 (a)) [137] , Zika virus (Figure 7 (b)) [70] , and Hepatitis B virus [138] . Here, the pathogen can bind to its natural target cell disguised as a target cell membrane-coated nanoparticle, which results in its immobilization, therefore disabling its ability to bind with the host target cells and, ultimately, removing its virulence. Other studies reported a similar phenomenon in HIV models, using plasma of CD4 + T cells to cloaking polymeric nanoparticles [137, 139] . Cell membrane-coated nanoparticles can also be used as multivalent nanovaccine platforms for antigen delivery to antigen-presenting cells (APCs). Ligands such as mannose can improve targeting of nanoparticles to APCs for instance by interacting with mannose receptors. In a recent study, mannose-modified RBC-derived membranes was used to coat plasmid DNA(pDNA)-loaded chitosan cores and improve transfection efficiency of antigen-encoding pDNA to APCs and elicit potent immune responses against fish viral disease (Figure 7 (c)) with prophylactic effects (Figure 7 (d)) [140].

The diversity of source cells and correspondent cell membranes have since inspired breakthrough developments toward management of a plethora of diseases, such as cancer, inflammation and infection [67, 76, 141] . According to the desired application, specific cell membrane coatings may be preferred on account of their biointerfacing properties. For example, while cancer cell membrane coatings may be preferred to target cancer cells via a homotypic targeting mechanism and enable enhanced cancer-targeted therapies [142, 143] , immune cells such as macrophages and neutrophils may be equally preferred for targeting cancer [144] [145] [146] [147] and manage inflammation and infection [103, 133, 135, [148] [149] [150] .

Hence, in the case of COVID-19, certain cells with intrinsic biofunctionalities may emerge as preferential source of cell membranes for coating nanoparticles, namely: (1) RBCs, providing prolonged blood circulation and immune evasion of payload-loaded nanoparticle cores (Figure 8 (a)) [151] ; (2) immune cells as inflammation and infection mediators, such as macrophages [135, 147] and neutrophils [150] , due to their innate recruitment to diseased tissues and intrinsic targeting ability for accumulation at inflammatory sites, and dendritic cells for lymph node targeting [152] (Figure 8(b) ); additionally, they may act as nanodecoys for SARS-CoV-2 immobilization and as inflammatory cytokine-absorbing nanosponges [19, 65] ;

(3) host epithelial cells, such as epithelial lung cells, as preferred targeted cells by SARS-CoV-2 and acting as nanodecoys mediating SARS-CoV-2 immobilization and neutralization, diverting SARS-CoV-2 from its natural targets (Figure 8(c) ); (4) platelets, owing to their mechanical flexibility and innate tropism to inflamed endothelium, injured tissue and vasculature (Figure 8(d) ) [153, 154] . Also similar to other diseases, the extracted cell membranes are used to produce cell membrane nanovesicles which can then be employed to coat nanoparticle cores yielding socalled cell membrane-coated nanoparticles, or used without further modification as cell membrane nanovesicles. So far, only host epithelial cell membrane-coated nanoparticles [19] , macrophage cell membrane-coated nanoparticles [19] , hybrid cell membrane nanovesicles [20] and leukocyte cell membrane vesicles [155] have been applied to COVID-19 management, particularly COVID-19 therapeutics, further discussed.

The virulence of SARS-CoV-2 is reliant on its interaction with protein receptors on the target cells upon entering the body. Hence, this interaction between pathogen and membrane is [70] . Copyright 2018, American Chemical Society. (c) Schematic illustration of the red blood cell-coated chitosan nanoparticles for plasmid DNA delivery to antigen-presenting cells. (d) Prophylactic effects of the constructed nanovaccine in zebrafish, 70 days after vaccination. P values were calculated by logrank (Mantel−Cox) test (*P < 0.05, **P < 0.01). Adapted with permission from [140] . Copyright 2020, American Chemical Society. mechanistically similar to that of the more well-defined infectious diseases, and conventional therapeutic approaches can also be applied in this situation. In this regard, a recent strategy encompassed the preparation of cell membrane-based nanovesicles as nanodecoys which can act as virus-trapping cell-like structures for virus immobilization and cytokine neutralization [20] . Briefly, 293 T genetically-engineered human embryonic kidney 293 T cells were genetically engineered to expose ACE2 protein. Then, ACE2-attached cell membrane vesicles were extracted and fused with cytokine receptorsenriched human myeloid mononuclear THP-1 cell membrane vesicles, originated from precursor human myeloid mononuclear THP-1 cells (Figure 9(a-c) ). The prepared cellular nanodecoys inherited native biological features, orientation and structure of source cells and showed combined SARS-CoV-2 immobilization and inflammatory cytokines (interleukin-6 (IL-6) and granulocyte−macrophage colony-stimulating factor (GM-CSF)) neutralization. In vivo suppression of acute pneumonia was additionally shown in acute lung inflammation mice models (Figure 9 (d-f)) [20] , suggesting interesting potentialities toward nanodecoy-assisted COVID-19 therapeutics. These cell membrane-derived nanovesicles successfully show the multifunctionality of biomimetic nanosystems via SARS-CoV-2 binding and immobilization combined with cytokine neutralization upon interaction with membrane-exposed cytokine receptors.

Other similar study reported ACE2-rich human embryonic kidney-293 T cells membrane-derived nanovesicles able to bind SARS-CoV-2 spike in means of biocompetitive inhibition and neutralize the virus, blocking its entry to the cytoplasm of host cells, namely renal tubular epithelial cells [156] .

Another study showed leukocyte-derived vesicles -leukosomes -(LKs) loaded with corticosteroid dexamethasone effectively improved pharmacokinetics of dexamethasone and attenuated SARS-CoV-2-triggered inflammatory response in a mice model of lipopolysaccharide (LPS)-induced endotoxemia [155] . The dexamethasone-loaded LKs were obtained from mouse macrophage J774 cell lines and consisted of macrophage cell membrane-based vesicles bearing an aqueous core enabling dexamethasone solubilization and an outer macrophage cell membrane-derived shell. When compared to free dexamethasone, the dexamethasone-loaded LKs could substantially suppress in vivo pro-inflammatory cytokines production and improve overall survival of mice models. The LKs per se are endowed with anti-inflammatory properties, namely augmenting anti-inflammatory cytokine levels (interleukin 10 and transforming growth factor beta (TGF-β)) and reducing pro-inflammatory ones (interleukin 6, interleukin 1b and transforming growth factor alpha (TNF-α)) [149].

Once a nanoparticle core is able to provide additional stability in biological environments when compared to sole cell membrane vesicles, a similar strategy was employed this time with polymeric nanoparticle cores. In this study, nanosponges composed of human-cell-derived membranes, which are sourced from cells that are naturally targeted by SARS-CoV-2, were wrapped around PLGA cores. The hypothesis of the study was that upon adherence to the nanosponges, SARS-CoV-2 is immobilized and disabled, and, therefore, it can no longer bind to its cell targets [19] . Nanosponges were either based on human lung epithelial type II or human macrophage cell membranes. The report showed that although both nanosponges exhibited activity against COVID-19, the macrophagebased nanosponges may have greater potential as a therapy. This is attributed not only to their ability to disable the viral efficacy, by reducing the viral load in the body, but also to their added ability to address the severe and sudden inflammatory response at later stages of COVID-19, due to the macrophages' intrinsic immunological functions [19] ( Figure  10) . Importantly, these nanosponges may not only maintain their therapeutic potential upon SARS-CoV-2 mutation but also have a transferable application to other viral diseases as long as the target cells remain the same, which constitute two major advantages when compared to conventional COVID-19 therapeutics. Regarding preclinical safety, no haemotoxicity or abnormal immune cell infiltration were detected after intratracheal administration of the nanosponges in mice.

The viral spike protein responsible for the pathogenesis of COVID-19 can be divided into S1 and S2 subunits after degradation, where the S1 subunit is responsible for recognizing host receptors, and S2 subunit mediates viral fusion into the cytoplasm [157] . The S1 binds to ACE2 gaining entry into the cells [157, 158] . In order to block the virus entry, cell membrane-coated nanoparticles based on the membrane of human embryonic kidney-239 T cells overexpressing human ACE2 (HEK-293 T-hACE2) have been developed to competitively bind the S1 proteins, thus blocking SARS-CoV-2 binding onto the cell membrane and subsequent entry into its targeted cells. The study showed that these biomimetic nanocarriers adsorbed the SARS-CoV-2 S pseudovirons onto their surface as expected, and indeed blocked viral entry into the cytoplasm, thus disabling virulence [157] .

The experimental studies described in this section so far encompass the application of cell membrane-coated or cell membrane-based nanoparticles as decoys for virus immobilization and inflammation reversal (Figure 11(a) ). However, other strategies could be possible undertaken toward COVID-19 treatment by enhancing antiviral drug delivery and pharmacokinetics by performing drug loading directly to the membrane or into the nanoparticle cores, similarly to studies reported so far in a wide range of diseases ( Figure  11 (c)) [76] .

Manipulating immune responses via a vaccine approach to battle COVID-19 has also been receiving growing attention. Inspiration from previous studies within the biomedical field covering cell membrane-coated nanoparticles as nanovaccines draw promising potentialities for further application to COVID-19 vaccination. In this case, immunization via SARS-CoV -2-derived antigens-coupling onto cell membranes could be of utmost relevance to boost vaccine development for COVID-19 prevention, building on integrated nano-based and biomimetic strategies, as reported for other infectious diseases. Immunoadjuvants can also be added to expand immune responses, loaded either in the nanoparticle core, or installed in the cell membrane, see for instance ( Figure 11(b) ). Another possibly strategy may consist of tuning targetability of cell membrane-coated nanoparticles by attaching targeting ligands to direct nanoparticles to particular tissues and cells and increase target specificity ( Figure 11 ).

Elucidating the in vivo safety of nanoparticles regardless of the biomedical applications is of paramount relevance as it may provide relevant cues on in vivo behavior and potential deleterious impact of nanoparticles in biological systems [159] . Hence, new data is urgently needed to improve the potentialities, safety and clinical translation of nano-based systems to counter back COVID-19 infection, a subject receiving particular attention in current times [160] . Toxicity assessment of cell membranebased nanoparticles is still at an early stage, particularly when referring to COVID-19 applications, due to the low amount of studies reported so far and lack of emphasis on toxicological profile owing to the novelty of this technology ( Table 2) .

While the biomimetic facet of cell membrane-based nanosystems are known to improve their biocompatibility toward biological systems due to their endogenous cellderived constituents which are the ultimate source of contact with the majority of in vivo environment -either functioning as cell membrane coatings to nanoparticle cores or as cell membrane nanovesicles bearing an aqueous core -it is not exactly clear the potential long-term impact of these nanosystems in humans. The sum of evidence so far has pointed toward their relatively safe profile [19, 156] ; however, in vitro and in vivo models and the respectively. In all data sets, n = 3. Data are presented as mean ± standard deviation. Horizontal dashed lines mark the zero levels. IC 50 values were derived from the variable slope model using GraphPad Prism 8 ™ . Adapted with permission from reference [19] , copyright American Chemical Society (2020).

EXPERT OPINION ON DRUG DELIVERY experience settings are distinct, which can difficult further comparability of results. Undoubtedly, more data specifically concerning the safety of these nanosystems is urgently needed.

The bioinspired technology, and wealth of choice in bioinspired membrane-coated nanocarriers, coupled with the preexisting promise from other applications makes cell membranebased nanoparticles a potentially real frontrunner in the development of new therapeutic and vaccination/prophylaxis approaches toward COVID-19 management. These innovative nanosystems have been described so far to block SARS-CoV-2 entry and replication in host cells and to reduce inflammation by cytokine capture, thus able to attenuate cytokine storm; and function as drug delivery nanosystems bearing high antiviral efficacy. Despite cell membrane-based nanoparticles have been widely explored toward several biomedical applications, the amount of data available on in vivo studies and regarding in vivo safety is still scarce, particularly when considering potential anti-COVID-19 applications.

Nevertheless, as more delivery technologies are developed and translated, the pathway will open wider, and it is certain that membrane-cloaked nanosponges and nanodecoys will play a pivotal role in these future biomedical interventions and therapies. Due to the lockdown of many laboratories globally, and still to this day, progress into the use of these technologies is hindered, but it is being expected that further information, as to their potential as well as translation, will be realized for application in COVID-19 cases within the coming years.

The COVID-19 pandemic has reshaped the present times calling for urgent and effective health and socio-sanitary responses to counteract this deadly outbreak. As the pandemic expands across the globe, enhanced research efforts across multidisciplinary fields are helping to rapidly gain more information on how the SARS-CoV-2 resulting in COVID-19 Figure 11 . Potential applications of cell membrane-coated nanoparticles as biomimetic and multifunctional systems for COVID-19 therapeutics and vaccination. (A) Nanodecoys composed of SARS-CoV-2 target cells' membrane provide a strategy to divert SARS-CoV-2 from its target cells and diminishing its infectivity. Nanodecoys are also able to reduce inflammatory processes via cytokine neutralization (B) SARS-CoV-2 vaccination can be composed of SARS-CoV-2 antigens coupled into or onto the cell membrane to achieve maximum exposition and delivery, as well as potentially benefiting from immunoadjuvant-mediated enhanced immune responses. (C) Both hydrophilic and hydrophobic drugs can be loaded in the nanoparticle core, and cell membranes provide also a reservoir for hydrophobic drug incorporation on account of their lipidic nature. Alone or in combination, these strategies may undergo substantial improvements by finetuning targeting affinity of cell membrane coatings by either ligand-coupled active targeting strategies, inherited surface self-markers (e.g. CD47 in the case of red blood cells) and immune cell membrane coatings. works. Together with several approaches that have been underlined to better understand SARS-CoV-2 nature and infectivity, the current anti-COVID-19 therapeutic or prophylactic arsenal consists of small drugs, antibody-based compounds and vaccines. Nano-based approaches constitute an effective and stimulating avenue to improve therapeutic effect and vaccination (prophylactic or therapeutic) potency of conventional strategies delineated for COVID-19 management, by improving pharmacokinetics, pharmacodynamics and safety. Multivalence benefits of nano-based delivery systems may augment neutralization potency as compared to monovalent binders, and improve vaccination as well. Further, unlike some biologics, biomimetic nanotechnologies can be manufactured at speed and scale -which constitutes an assertive goal when there is global demand. In this regard, more sophisticated and multifunctional strategies have been receiving increasing importance to maximize efficacy of COVID-19 prophylaxis and treatment, inspired by the biological interactions and cellular components. In this regard, cll membrane-based nanoparticles have received substantial attention recently as biofunctional, multivalent, tunable and biocompatible systems capable of acting as virusneutralizing nanodecoys and with promising future potential for building refined nanovaccines, as well as refined drug delivery systems bearing ultra-targeting features for ideal site-specific action. When experimental or theoretical structural information is combined with biomimetic nanotechnologies, the timeline to develop first-line, target-specific vaccines or therapeutics to emerging infectious disease is unmatched in potential.

Cell membrane-based nanoparticles strategies on fighting SARS-CoV-2 have relied so far on a nanodecoy-based approach in which the virus recognizes and binds to host cell membranes either coating a nanoparticle core or in the form of nanovesicles, followed by virus immobilization and/or neutralization and blocking its infectivity. These strategies are interesting once they function as multifunctional cellular traps by disguising nanoparticles as natural SARS-CoV-2 target cells thus mimicking its biological responses.

Despite cell membrane-based nanoparticles are known to preserve the biofunctionality of the parent cells, additional functionalization with targeting ligands may impart maximized biomimicry, and magnify their tissue targeting properties. Several methods have been described so far including the broadly used lipid insertion method, as well as metabolic engineering and genetic modification methods. Membrane hybridization by fusing to cell membranes form distinct cell sources can endow cell membrane coatings with additional functionalities and expand their versatility [106] . Targeting capabilities of the nanoparticles to various cellular and subcellular sites can be used to improve the overall therapeutic efficacy and reduce the chances of resistance development.

Mannose-targeted cell membrane coated nanoparticles, for instance, have been explored to target antigen presenting cells expressing mannose receptors. Besides enhancing antigen delivery to the lymph node by a nano-based Abbreviations: ACE-2: Acetilcolinesterase-2; THP-1: human monocytic cell line; HBSS: Hank's balanced salt solution.

EXPERT OPINION ON DRUG DELIVERY strategy, the additional functionalization with mannose increased dendritic cell targeting, contributing to maximized antigen processing, immune system activation and enhanced anticancer [107] or antiviral [140] performance. In the light of these reports, a similar technological strategy could possibly be carried out for SARS-CoV-2 long-term immunization ( Figure 11 ). According to the aforementioned, of considerable interest is the provenience of cell membranes and respective intrinsic cell membrane biofunctionalities transferred onto nanoparticle cores. While RBC membrane coatings have been the most studied so far, other membrane types endowed with lymph node targeting features hold particular relevance, as recently reported with dendritic cell membrane coatings able to strengthen cellular immunity for cancer immunotherapy purposes [161] . This strategy could potentially refine the scope of vaccines for COVID-19 prevention, which could pass by coating nanoparticle cores with dendritic cell membranes for achieving improved lymph node targeting and maximize interaction of antigen/toxoid with antigen-presenting cells (APCs).

Similar to outer membrane vesicles (OMVs) as natural bacteria's lipid bilayer-mimetics in terms of composition and function, perhaps an approach involving SARS-CoV-2 envelopederived nanovesicles -virosomes -could be of interest to design multivalent antigen-displaying biomimetic nanoplatforms for COVID-19 vaccination and prophylaxis [162] . These nanovesicles may undergo successful surface functionalization through hybridization with bifunctional cell membrane vesicles to assemble hybrid membrane-based nanovesicles which can be used isolated or as a coat to nanoparticle cores.

As with all nanomedicines, however, caution must be paid when proceeding, as regulatory frameworks are not sufficiently adapted in order to define the long-term effects of nanoparticles, which hinders their ability to become rapidly translated to meet the demands of the pandemic. Key issues to be surpassed include the variability of the cell membrane sources, the amount of available material and complex characterization procedures which can be hopefully -and partially -overcome through simpler standardized production and characterization protocols together with the generation of more knowledge regarding in vivo stability and safety of these nanosystems. Moreover, the lack of in vivo studies so far calls for new data for better conclusions regarding the shortand long-term potential of cell membrane-based technology for COVID-19 management, and is a reflex of its novelty.

A key issue regarding cell membrane-based nanovaccines for COVID-19 prophylaxis is also the durability and adaptability toward potential viral mutations, as reported to other vaccines [163] .

This work received financial support from the grants SFRH/BD/148771/ 2019 (to MP-S) and PTDC/BTM-MAT/4738/2020 (to ACP-S) from Fundação para a Ciência e Tecnologia (FCT). This work is also supported in part by a grant from the National Science Foundation NSF CMMI-2027668 (to NFS). The authors GC, SOM-C would like to acknowledge the funding support provided by the Federico Baur Endowed Chair in Nanotechnology (0020240I03)

NF Steinmetz is a co-founder of Mosaic ImmunoEngineering Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose ORCID Miguel Pereira-Silva http://orcid.org/0000-0003-4276-5063 Clare Hoskins http://orcid.org/0000-0002-7200-0566 Francisco Veiga http://orcid.org/0000-0002-1041-0068 Ana Cláudia Paiva-Santos http://orcid.org/0000-0003-2710-6000

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