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Delivery of cancer therapies by synthetic and bio-inspired nanovectors

Delivery of cancer therapies by synthetic and bio-inspired nanovectors Background: As a complement to the clinical development of new anticancer molecules, innovations in therapeutic vectorization aim at solving issues related to tumor specificity and associated toxicities. Nanomedicine is a rapidly evolving field that offers various solutions to increase clinical efficacy and safety. Main: Here are presented the recent advances for different types of nanovectors of chemical and biological nature, to identify the best suited for translational research projects. These nanovectors include different types of chemically engineered nanoparticles that now come in many different flavors of ‘smart’ drug delivery systems. Alternatives with enhanced biocompatibility and a better adaptability to new types of therapeutic molecules are the cell-derived extracellular vesicles and micro-organism-derived oncolytic viruses, virus-like particles and bacterial minicells. In the first part of the review, we describe their main physical, chemical and biological properties and their potential for personalized modifications. The second part focuses on presenting the recent literature on the use of the different families of nanovectors to deliver anticancer molecules for chemotherapy, radiotherapy, nucleic acid-based therapy, modulation of the tumor microenvironment and immunotherapy. Conclusion: This review will help the readers to better appreciate the complexity of available nanovectors and to identify the most fitting “type” for efficient and specific delivery of diverse anticancer therapies. Keywords: Cancer therapy, Vectorization, Nanomedicine, Drug delivery, Targeting, Virus, Nanoparticle, Vesicle Introduction molecules such as hydrophobic drugs, radioisotopes, toxins Cancer causes approximately 10 million deaths per or nucleic acids cannot be injected systemically to patients year worldwide for around 18 million new cases [1]. because of their instability or of extensive off-target effects. Advanced understanding of cancer biology and continuous These limitations can be overcome through vectorization improvement of treatments such as radiotherapy, chemo- using nanocarriers that will increase drug solubility and therapy and more recently immunotherapy have steadily bioavailability, improve the targeting of the cancer micro- ameliorated patient survival over the years. In many cases, environment, augment local drug concentration in tumors these treatments remain associated with adverse effects and potentiate the efficacy of therapeutic combinations and limited efficacy due to a lack of tumor specificity. [2, 3](Fig. 1). Resistances to single treatments are commonly addressed Specific targeting, which is key to increase treatment by combination therapies that can further increase the risks efficacy while reducing detrimental off-target effects, of life-threatening toxicities. Moreover, some categories of remains a major scientific challenge in multiple areas of therapeutic research. In cancer therapy, vectorization approaches have recently diversified with the development * Correspondence: of new families of nanovectors (1 to 1,000 nm) created by Tina Briolay and Tacien Petithomme contributed equally to this work. chemical engineering (e.g. nanoparticles) [3]or derived Université de Nantes, Inserm, CRCINA, F-44000 Nantes, France © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated in a credit line to the data. Briolay et al. Molecular Cancer (2021) 20:55 Page 2 of 24 Fig. 1 Advantages of vectorization for delivering cancer therapies. The clinical efficacy of therapeutic molecules (e.g. chemotherapeutic drugs, radionuclides, nucleic acids, antibodies) relies on efficient tumor delivery and limited off-targeting. Nanovectors of different natures (e.g. nanoparticles, extracellular vesicles, viruses) can improve the transport of these molecules in the bloodstream by increasing their solubility, half-life and bioavailability, and by helping the crossing of biological barriers. Tumor delivery is also enhanced by improved targeting of the tumor microenvironment, leading to the accumulation of the therapeutic molecules in the tumors and thus potentiating the use of combination therapies from the biological world (e.g. bacteria, viruses, extracellu- radioisotopes, proteins, nucleic acids) and make them lar vesicles) [4]. Although this adds to the complexity of adapted to different biological and clinical situations. drug development, efficient vectorization appears as A clear understanding of the advantages and limitations of essential to further improve the safety and efficacy of both each of these nanovectors (Table 1) to transport different current and future cancer therapies. In this review, we therapeutic agents (Table 2) and of their evolving potential chose to focus on nanovectors that are able to protect and will help developing better vectorization approaches in the to carry therapeutic payloads to tumors following a sys- future. temic injection. This does not include antibody-mediated vectorization [5], cancer vaccination strategies [6]or Types of nanovectors vectorization for imaging [7] – for instance for guided sur- Nanoparticles gery – which have been reviewed elsewhere. We first Chemically engineered nanoparticles form a vast class of introduce the various families of nanovectors available nanovectors with a wide variety of structures, sizes and today, including the different subtypes of organic and in- compositions [8, 9] (Fig. 2). Among the inorganic family, organic nanoparticles (Fig. 2), cell-derived extracellular the most studied are metallic (e.g. gold, iron oxide) vesicles (EVs), virus-like particles (VLPs) (e.g. plant and nanoparticles that display unique optical and electronic animal viruses, bacteriophages), oncolytic viruses (OVs) properties particularly favorable for biomedical imaging and bacterial minicells (Figs. 3 and 4). These vectors [10]. Because of their solid core, drug functionalization display different physical and structural properties that consists in surface bonding and exposes conjugated dictate their abilities to be coupled to different types drugs to both degradation and exchange dynamics in the of therapeutic molecules (e.g. chemotherapeutic drugs, bloodstream. Their use in therapy is also limited by a Briolay et al. Molecular Cancer (2021) 20:55 Page 3 of 24 Fig. 2 Chemically engineered nanoparticles for cancer therapy. This class of nanovectors is commonly divided between inorganic and organic nanoparticles. Inorganic nanoparticles (e.g. metallic, silica, carbon, quantum dots) are characterized by a high stability, a low biodegradability and intrinsic electronical and optical properties suitable for cancer imaging and theranostics. Because of their solid core, therapeutic molecules are generallyconjugated on their surface and may be exposed to rapid degradation in vivo. Organic nanoparticles (e.g. lipid-based, macromolecular assemblies) exhibit a lower stability but a good biocompatibility and multiple possibilities of drug functionalization on their surface or their inner space. Hybrid nanoparticles combine the advantages of both inorganic and organic families to improve the biocompatibility and the stability of the nanovector low biodegradability. Mesoporous inorganic nanoparticles their unmatched biocompatibility [8, 14, 15]. They basic- – mostly biodegradable, silica-based – constitute an alter- ally consist in lipid monolayered (i.e. micelles) or bilayered native to protect drugs within a porous structure but their (i.e. liposomes) nanovesicles and can vectorize a broad safety profile still needs characterization [11, 12]. On the range of molecules with distinct physicochemical proper- other hand, the organic nanoparticle family exhibits better ties; hydrophobic drugs can be embedded within the lipid biocompatibility and biodegradability, making those more bilayer of liposomes or loaded in the core of micelles while suitable for therapeutic applications. The first organic hydrophilic drugs are either entrapped in the aqueous subfamily encompasses natural (e.g. protein- and core of liposomes or displayed on their surface [16, 17]. polysaccharide-based) and synthetic (e.g. polylactic acid However, lipid-based nanoparticles still face several limita- derivatives, dendrimers, fluorescent organic nanoparticles) tions among which a low loading capacity and a relative macromolecular nanoassemblies (also improperly called lack of stability leading to drug leakage. New hybrid nano- polymeric nanoparticles) that possess a good stability and particles have recently been developed to combine the display numerous free functional groups endowing them respective advantages of the different subfamilies, namely with a high loading capacity [8, 13]. These properties solid-lipid, hybrid polymer-lipid [18] and hybrid organic- explain the growing interest for such nanoassemblies in inorganic nanoparticles [19]. cancer therapy even if the in vivo characterization of each Nanoparticular vectorization is traditionally believed of their subunits remains challenging. The second organic to take advantage of the enhanced permeability and subfamily contains lipid-based nanoparticles that are the retention (EPR) effect that results from the abnormal most represented in preclinical and clinical studies due to tumor vasculature causing preferential extravasation and Briolay et al. Molecular Cancer (2021) 20:55 Page 4 of 24 Fig. 3 Biological and bio-inspired nanovectors for cancer therapy. These nanovectors have been derived from different types of organisms and exhibit high biocompatibility and extensive engineering possibilities. Extracellular vesicles derive from eukaryotic cell membranes and naturally transport different types of biomolecules (e.g. proteins, RNA). Bacterial minicells are achromosomal 400-nanometer vesicles that can be generated by genetic engineering of bacteria and have been recently used to vectorize various types of therapeutic molecules. Virus-like particles are basically viruses (e.g. bacteriophages, plant viruses, eukaryotic viruses) stripped of their replicative capacity; they exist as naked or enveloped capsids and sometimes require a non-replicative template genome for their assembly. On the contrary, oncolytic viruses are tumor-specific, live- replicating viruses with intrinsic cytotoxic and immunoactivating properties; they can equally be naked or enveloped and may be modified by genetic engineering to transport therapeutic transgenes that will be expressed exclusively by infected malignant cells increased concentration of nanoparticles in tumors both the tumor neovasculature and some malignant [9, 20, 21]. Recent evidence also supports the exist- cells – was also reported to improve the specific ence of an additional active uptake process through extravasation of nanoparticles in tumors [23, 27]. endothelial cells [22]. However, even though the Overall, nanoparticles act as multimodal platforms global biodistribution of nanoparticles seems to rely that can be extensively engineered to improve both mostly on these mechanisms, only actively targeted tumor targeting and the delivery of combined treat- nanoparticles efficiently infiltrate tumors and enter ments to malignant cells; they are perfectly suited to in- malignant cells [2, 23]. This requires coupling nano- crease both the half-life of therapeutic molecules in the particles to targeting molecules – directed against bloodstream and their concentration in tumors while surface antigens overexpressed on tumor cells – in- lowering their systemic toxicity [3]. Nevertheless, they cluding but not limited to proteins (e.g. antibodies face several biological barriers that have limited their [24, 25]), aptamers [26], peptides [27] or polysaccha- clinical use so far (Fig. 5). These hurdles can however rides [28]. An emerging alternative modality of active be overcome by rational engineering [3, 9]. As such, tumor targeting is the external magnetic guidance of clearance by the mononuclear phagocytic system is metallic nanoparticles to promote preferential tumor usually diminished by functionalizing nanoparticles extravasation [29]. Their coupling to iRGD peptides with non-immunogenic hydrophilic polymers such as – recognized by the α β integrin overexpressed on polyethylene glycol (PEG) or zwitterionic ligands [30]; v 3 Briolay et al. Molecular Cancer (2021) 20:55 Page 5 of 24 Fig. 4 Biogenesis of biological nanovectors. Biological nanovectors are either derived from prokaryotic (bacterial minicells) or eukaryotic (extracellular vesicles) cells, or from viruses (oncolytic viruses and virus-like particles). Bacterial minicells are achromosomal vesicles obtained upon genetic engineering (deletion of the Min operon) from ectopic septation of Gram-positive or Gram-negative bacteria. Extracellular vesicles are produced by all eukaryotic cells by outward budding of the plasma membrane (microvesicles) or through inward budding and exocytosis (exosomes). Regarding viruses, whereas live-attenuated oncolytic viruses carry a complete genome and thus retain a replicative capacity specific for transformed cells, virus-like-particles are only constituted of structural proteins and are consequently not competent for replication this prevents interactions with immune cells – thereby to study the effect of the protein corona formation enhancing their half-life in blood – but can also de- around nanoparticles, as it can drastically impact their crease internalization by tumor cells. Of note, PEG can stealthiness and tumor uptake [33–35]. Tunable drug also be recognized by-anti-PEG antibodies that will im- release solutions have also been created to promote a pair vectorization efficacy and may generate immune- specific delivery of packaged drugs exclusively in tu- related adverse effects [31]. To improve the cellular in- mors.Hence,so-called ‘smart’ drug delivery systems take of PEGylated nanoparticles within tumors, stealth enclose pH-, enzyme-, heat- or photo-sensitive mole- polymer coatings that specifically dissolve in the tumor cules which conformations change in tumors to specif- microenvironment (TME) have been developed [32]. ically destabilize the nanoparticle structure and release Stealthiness can also be improved by entrapping nano- the therapeutic cargo [9, 36]. To improve nanoparticle tis- particles into cellular membranes to mimic biological sue penetration and diffusion through the dense extracel- vesicles [19]. A lot of work has been performed lately lular matrix (ECM) in tumors, several combinations of Table 1 Main properties of the different families of nanovectors Nanovector Biocompatibility Stealth Immunogenicity Ease of Systemic Frequent Replicative Stability Standardized Cost family retargeting injection off-targets production Inorganic Very low Good Low High Possible Liver, No Good Adapted $$$ nanoparticles spleen Organic Good Good Low High Adapted Liver, No Medium Feasible $$ nanoparticles spleen Extracellular High High None Low Adapted Liver No Low No $$$ vesicles Bacterial High Low Medium Medium Adapted Liver No Medium Feasible $ minicells Virus-like High Medium Medium High Adapted Liver No Medium Feasible $$$ particles Oncolytic High Medium High Low Possible Depends Yes Low Difficult $$$ viruses on virus tropism Briolay et al. Molecular Cancer (2021) 20:55 Page 6 of 24 Table 2 Suitability of the different families of nanovectors for the vectorization of anti-cancer therapeutics Nanovector family Chemotherapy Radiotherapy Gene therapy RNA interference TME modification Immunotherapy Nanoparticles +++ ++ + + + + Extracellular vesicles+- + ++ NT + Bacterial minicells ++ NT NT ++ NT NT Virus-like particles + NT +++ ++ NT + Oncolytic viruses - + +++ ++ +++ +++ +++: optimal; ++: adapted; +: feasible; -: not adapted. NT: never tested, TME: tumor microenvironment. expected to be similar to RNA interference ECM-modifying molecules and nanoparticles are also cur- Biological and bio-inspired nanovesicles rently under investigation [37]. Finally, a major pitfall for The biological world provides attractive alternatives to vectorization with nanoparticles is their trapping in endo- artificial lipid-based nanoparticles. Extracellular vesicles lysosomes after endocytosis, which exposes the thera- (EVs) are naturally occurring vesicles produced by peutic cargo to degradation. Available solutions include eukaryotic cells and play important roles in intercellular coupling nanoparticles to endosomal escape domains or communications [39]. They naturally package a broad proton sponges to destabilize endosomes and promote range of cargos, from nucleic acids to proteins or lipids. drug release toward the cytoplasm [38]. There are two main types of EVs at the nanometer scale, Fig. 5 From the blood to the tumor cell: the difficult journey of nanovectors. Systemically injected nanovectors face several biological barriers to reach the tumor microenvironment and exert their therapeutic effect in malignant cells. First, filtering organs such as the liver (for nanovectors > 5 nm) or the kidneys (for nanovectors < 5 nm) eliminate an important fraction of the injected nanovectors. Nanovectors then extravasate from the bloodstream to the tumor either because of an increased vascular permeability (Enhanced Permeability and Retention effect) or by active transcytosis through endothelial cells. The nanovectors have to overcome the interstitial pressure and to diffuse in the extracellular matrix to reach tumor cells. This can be partially improved by active targeting strategies through nanovector engineering. Once reaching the cancer cells, nanovectors can be internalizedby several mechanisms (e.g. passive or virus-mediated fusion, endocytosis, macropinocytosis) depending on their origin, size, composition and functionalization. The final difficulty consists in delivering the therapeutic cargo in the appropriate cellular compartment – generally the cytoplasm – to achieve optimal therapeutic efficacy. This usually requires further vector engineering (e.g. endosomal escape domains, pH-sensitive moieties), in particular for non-biological nanoparticles.EVs: Extracellular Vesicles; VLPs: Virus-Like Particles; OVs: Oncolytic Viruses Briolay et al. Molecular Cancer (2021) 20:55 Page 7 of 24 namely microvesicles (50 nm to 1 μm) and exosomes with different structures, charges and solubilities in an (50 to 150 nm) that differ by their biogenesis and easier way than with lipid-based nanoparticles [55, 59]. composition. Microvesicles directly bud outward of the They display a high loading capacity – up to 1,000 times plasma membrane while exosomes are generated from higher than liposomes – following simple drug import- the inward budding of endosomal membranes and are ation through the outer membrane via the non-specific released in the extracellular environment by exocytosis FadL or OmpW channels. To confirm their interest in (Fig. 4). Because of their low immunogenicity and their cancer therapy [60, 61], comprehensive studies are still efficient intake by cells [40], EVs have been investigated needed to better characterize their properties, among as drug nanocarriers for cancer therapy [41]. Therapeutic which their immunogenic profile. Their safety however drugs can be loaded either directly into pre-formed pleads for further developments, as was demonstrated in vesicles or through modification of the EV-producing cells three recent phase I clinical trials that tested Epidermal (e.g. drug exposure, transfection) to entrap the cargo into Growth Factor Receptor (EGFR)-targeted minicells loaded EVs during their formation [42, 43]. Although still contro- with either paclitaxel [62], doxorubicin [63]or miRNA versial [44], EVs are suspected to possess inherent target- mimics [64] in patients with end-stage solid cancers, ing capacities depending on their progenitor cell type [45]; glioblastoma or mesothelioma, respectively. tumor cell-derived exosomes thus appear to preferentially home to their cell types of origin in vitro compared with Virus-like particles untargeted liposomes [46]. As for liposomes, the surface Viruses are extensively studied in therapeutic vectorization of EVs can be modified with targeting molecules or PEG due to their active cell entry mechanisms, biocompatibility [47]. Nevertheless, the lack of content standardization and and well-characterized structures. Virus-like particles of large-scale production methods still hinders their clin- (VLPs) were developed to mimic animal, plant or bacteria ical use; the development of EV-like nanovesicles, which viruses without retaining the ability to replicate in human are basically liposomes enriched with membrane proteins cells [65] (Figs. 3 and 4). They are viral capsids with an to enhance cellular intake, is expected to help overcoming icosahedral or filamentous structure composed of self- some of these limitations [48]. A derivative from this idea assembled proteins. Their diameters range from 25 (e.g. are “virosomes” (150 to 500 nm) that are composed of a parvoviridae) to several hundred (e.g. herpesviridae)nano- synthetic lipid bilayer containing viral or parasitic meters and they can contain a non-infectious genome fusogenic glycoproteins [49, 50]. Those take advantage of composed of single- or double-stranded RNA or DNA the ability of viral envelopes to recognize the targeted cells [66]. Icosahedral VLPs can be used as genome-free parti- and to promote direct fusion with the plasma membrane, cles such as the ones derived from the MS2 bacteriophage hence skipping the potential degradation of the encapsu- [67], which spontaneously assemble during protein lated cargo into late endosomes after endocytosis (Fig. 5). production in bacteria, or from the cowpea mosaic virus Other strategies use cell-derived nanovesicles to camou- (CPMV) [68]. On the contrary, filamentous VLPs derived flage other types of vectors (e.g. nanoparticles, viruses) to from plant viruses and bacteriophages generally require a take advantage of their intrinsic properties and to escape template genome for capsid proteins to assemble around it neutralizing antibodies [51–54]. and form a rigid or flexible tube which length and width The trend to exploit bio-derived nanostructures for are determined by the capsid protein and the genome size. cancer therapy extends to different families of patho- In addition, some viruses (e.g. retroviridae)presentan gens. Bacterial minicells (200 to 400 nm) are achromoso- envelope composed of an external lipidic membrane mal vesicles produced by bacteria upon ectopic septation acquired while budding from the host cell surface [69]. As [55] (Fig. 4), an asymmetric division obtained by deleting VLPs contain non-self proteins and potential pathogen- the Min operon [56]. Minicells can be produced from associated molecular patterns, they can be immunogenic Gram-positive and Gram-negative bacteria and contain and were mostly assessed as anti-cancer immuno- all the molecular components of the parent cell except stimulatory treatments [70]. Their use as vaccines showed for the chromosome. Because of their vesicular struc- a good safety profile that makes them suitable for future ture, they are an alternative to lipid-based nanoparticles use as nanovectors. Nevertheless, repeated treatments for cancer therapy (Fig. 3). Although Gram-positive could promote the generation of antibodies and clearance minicells are negative for lipopolysaccharides (LPS) and by immune cells resulting in decreased tumor delivery. may be ultimately more adapted for clinical use, most Capsid PEGylation or elimination of immuno-dominant studies have used Gram-negative minicells that can be epitopes can however limit these issues [71]. easily redirected to cancer-specific receptors (e.g. HER2/ Because of their viral nature, VLPs are perfectly neu) with bispecific antibodies targeting both the LPS adapted to the delivery of therapeutic nucleic acids [72] O-antigen on minicells and a tumor marker [57, 58]. but empty capsids can also be modified to transport Bacterial minicells can package a wide variety of molecules other types of molecules. As such, the fixed structures of Briolay et al. Molecular Cancer (2021) 20:55 Page 8 of 24 VLPs allow for extensive genetic and chemical engineer- a diversity of immune cell types involved in the anti- ing. Examples include tobacco mosaic virus VLPs that tumor responses [86, 92]. After two decades, more than a can be loaded by simple infusion and ionic interactions hundred trials and few regulatory approvals for clinical with their inner surface [73], the hepatitis B virus capsid use [93–95], they have demonstrated a very good safety that can be disassembled and re-assembled to capture a profile but a somewhat modest therapeutic efficacy in compound [74], or the functionalization of MS2 VLPs humans. by inserting genetically a cystein residue in the capsid To improve their intrinsic anti-cancer properties, OVs [75]. Interestingly, filamentous VLPs show a natural are commonly armed to vectorize therapeutic transgenes biodistribution to tumors after systemic injection, which that will be expressed by infected malignant cells in the could be mediated by their physical behavior in the TME, thereby making them bona fide nanovectors [96]. tumor microvasculature [76, 77]. Non-human virus- Viruses have evolved to deliver efficiently their genome based VLPs did not evolve to recognize human cell re- in host cells and are thus perfectly designed to vectorize ceptors; they produce less off-target effects but require nucleic acids (Fig. 5). The first OV to be approved by genetic or chemical retargeting to malignant cells. Com- the US and EU regulatory agencies in 2015 was the mon modifications involve the retargeting of VLPs with recombinant herpesvirus Talimogene laherparepvec (T- cancer-specific peptides [78], aptamers [75] or other VEC) that encodes the Granulocyte-Macrophage Colony- molecules [72, 79], or the pseudotyping of enveloped Stimulating Factor to enhance its immunostimulatory VLPs with exogenous proteins. Similarly, twelve properties [94, 97]. The transgene capacity of viruses is serotypes of adeno-associated viruses (AAVs) have been however limited by the fitness cost – the longer the gen- identified so far [80] and could be used to target differ- ome, the longer it takes to replicate – and the size limit of ent types of cancers. In addition, VLPs from plant or the viral particle; DNA viruses generally exhibit a higher bacteria viruses cannot easily escape human endo- transgene capacity than RNA viruses. OV replication cap- lysosomes and display lower transfer efficacy, even after acity allows both spreading of the transgene in the tumor retargeting [81–84]. Strategies similar to the ones used and its sustained expression over time [98]. As with VLPs, with nanoparticles for endosomal escape and cargo surface molecular coupling is theoretically possible – es- delivery are being tested to overcome these limitations pecially for non-enveloped viruses – to enable intracellular [78]. On the opposite, VLPs derived from human patho- delivery of drugs in specific cells. gens benefit from coevolution to achieve efficient gene The current standard for OV treatment is intratumoral transfer inside human cancer cells (Fig. 5). injection with the limit that only reachable tumors can be treated, but recent evidence of viral replication in tumors Oncolytic viruses following intravenous administration in patients have been Contrary to VLPs for which the non-replicative nature is reported [99–103]. Despite pre-existing immunity having a major determinant of their clinical safety and inter- no measurable effect on the therapeutic outcome after mediate immunogenicity, oncolytic viruses (OVs) display intratumoral injection, innate and adaptive immune re- all the properties of natural viruses except that their sponses against circulating viruses may restrict their efficacy replication is restricted to malignant cells [85] (Fig. 4). after intravenous administration [104, 105]. PEGylation of The diversity of OVs has been reviewed extensively OVs [106, 107] or switching OV species during the course elsewhere [86] and is summarized in Fig. 3. OVs are of treatment [108, 109] can improve stealthiness and either naturally attenuated viral strains or genetically enhance treatment efficacy. Enveloped viruses can also be engineered viruses that harness cancer hallmarks such as pseudotyped with different viral envelops [110–112], while altered metabolism, immunosuppression or resistance to changing the serotype of non-enveloped viruses could cell death that make tumors more sensitive than healthy evade the immune response [113–115]. Finally, the titration tissues to viral infections. Tumor cells also commonly of OVs by healthy cells after non-specific entry – distinct overexpress surface proteins that are used by some from their tumor-specific replication and killing – can be viruses for cell entry [87, 88]. For many oncolytic RNA answered by retargeting OVs to tumor-specific surface anti- viruses, tumor specificity mainly depends on defects in gens through genetic engineering. Advances made in the the innate antiviral pathways commonly acquired by field of nanoparticles for chemical modifications are also malignant cells during tumor evolution [89, 90], while expected to lead to alternative solutions [107]. DNA viruses can be modified with tumor-specific promoters [91]. Contrary to other nanovectors, the tumor Applications in cancer therapy specificity of OVs thus mostly relies on post-entry restric- Chemotherapy tion rather than selective entry through specific surface Cancer chemotherapeutics are a large family of chemical markers. They also exhibit therapeutic properties on their drugs [116] that affect highly proliferating malignant own as they can both directly kill tumor cells and activate cells and exhibit diverse modes of action from cell cycle Briolay et al. Molecular Cancer (2021) 20:55 Page 9 of 24 arrest to cell death induction and epigenetic modulation. Other types of nanovectors are currently studied to These molecules often lack tumor specificity and healthy transport and deliver chemical drugs to tumors (Table proliferative cells are frequently impacted, thereby 2). The characterization of VLPs at the atomic level causing different debilitating symptoms. Consequently, allows for precise chemical coupling strategies similar vectorization of chemotherapeutics is critical to improve to the ones used for nanoparticles. For example, their tumor specificity and diminish side toxicities. Here, doxorubicin coupling to Physalis Mottle virus icosahe- we present an overview of how the different families of dral VLPs [81] or to truncated hepatitis B virus core nanovectors can help bypassing the major limitations of antigen (tHBcAg) VLPs [138] improved both its cellu- chemotherapies, including their poor aqueous solubility, lar uptake and cytotoxicity against malignant cells. their lack of tumor specificity and the acquisition of re- Doxorubicin and mitoxantrone were also passively sistances. The advantageous physical properties of some loaded into CPMV [139] and filamentous plant vi- nanovectors that can be exploited in combinatorial strat- ruses VLPs [140–142] by exploiting for the latter the egies with chemotherapies are also discussed. negative charges of the inner side of the particles. Simple dissociation/association of tHBcAg allows for passive dual loading of polyacrylic acid (PAA) along Solving drug insolubility with doxorubicin that will be released at low pH Chemical drugs for cancer treatment vary widely by their when no longer retained by protonated PAA [79]. structures, charges and solubilities that can limit their EVs on their part display similar vectorization abilities clinical use, an illustrative example being the high as liposomes.Theywereshown forinstancetodeliver hydrophobicity of taxanes [117]. The nanomedicine doxorubicin [143]orpaclitaxel[144] in vitro to breast field however provides numerous solutions for drug or prostate cancer cells, respectively, or paclitaxel to vectorization whether they are hydrophobic (e.g. lung cancer cells after systemic administration in mice paclitaxel, cisplatin) or amphipathic (e.g. doxorubicin, [145]. Packaging of decitabine in erythro-magneto- 5-fluorouracil). As explained above, the diversity of hemagglutinin nanovesicles showed a specific delivery chemically engineered nanoparticles with variable to prostate cancer xenografts under in vivo magnetic loading and functionalization possibilities makes them guidance and a significant tumor mass reduction at a the most suitable for vectorizing chemotherapeutic lower dose than with free decitabine [146]. Among drugs [9, 118](Table 2). Hydrophilic drugs can be eas- the bio-inspired nanovectors, bacterial minicells may ily encapsulated inside liposomes, adsorbed in pores of be the more promising as they can incorporate a wide silica nanoparticles or conjugated on metallic or poly- variety of chemotherapeutic agents without drug ef- meric nanoparticles using reactive hydroxyl, carboxyl, flux up to several days [55]. Their encouraging early amino or thiol groups. Hydrophobic molecules are clinical results in two phase I clinical trials that used commonly loaded in micelles or solid-lipid nanoparti- EGFR-targeted bacterial minicells containing either cles or inserted in the lipid bilayer of liposomes. Nano- doxorubicin or paclitaxel to treat patients with ad- particles are also used to vectorize hydrophobic vanced solid tumors [62, 63] however need to be epigenetic modulators (e.g. inhibitors of histone deace- confirmed. tylases or DNA methyltransferases) to improve their pharmacokinetics and therapeutic efficacy [119–122]. Improving tumor specificity Macromolecular nanoassemblies and lipid-based nano- The lack of tumor specificity for chemotherapies causes particles have been used to vectorize almost all types off-target effects and limits clinical efficacy by decreasing of chemotherapeutics and several nanomedications drug concentration in tumors. For instance, doxorubicin have either already been approved by the FDA for can- displays elevated hematological and cardiac toxicities as cer treatment or are currently evaluated in clinical tri- a free molecule [147]. It has been vectorized as early as als [8, 123](Table 3). It is interesting to note that the 1990s in the first FDA-approved nanodrug Doxil®, cancers with very different profiles, from end-stage which is currently approved for the treatment of ovarian solid tumors to hematological malignancies, can be eli- cancer, multiple myeloma, metastatic breast cancer and gible to nanovectorization of chemotherapeutics. As an Kaposi’s sarcoma. Doxil® is composed of doxorubicin en- example, the nab-paclitaxel formulation (Abraxane®) – capsulated in untargeted, PEGylated liposomes that en- composed of paclitaxel fused to human albumin nano- able a high concentration of doxorubicin in tumors particles – has demonstrated improved safety and effi- correlated with a higher tolerability compared to free cacy compared to free paclitaxel [136] and is approved doxorubicin [148]. This formulation was followed by against non-small cell lung cancer, metastatic pancre- many other combinations of chemotherapeutic drugs atic cancer and as a second-line treatment for meta- with numerous types of nanoparticles [124]. As with the static breast cancers [137]. Doxil® liposomal formulation, their tumor specificity Briolay et al. Molecular Cancer (2021) 20:55 Page 10 of 24 Table 3 Representative examples of the advancement of nanovectors in cancer therapy Nanovector Therapy Drug administration Phase Cancer types Route of References family administration Organic Chemotherapy PEGylated liposomal doxorubicin Approved Ovary, Kaposi’s sarcoma, Intravenous [137] nanoparticles (Doxil®/Caelyx®) (1995) multiple myeloma Non-PEGylated liposomal doxorubicin Approved Breast Intravenous (Myocet®) (2000) Albumin particle-bound paclitaxel Approved NSCLC, breast, pancreas Intravenous (Abraxane®) (2005) PEGylated liposomal irinotecan Approved Pancreas Intravenous (Onivyde®/MM-398®) (2015) Non-PEGylated liposomal cytarabine:daunorubicin Approved AML Intravenous (VYXEOS®/CPX-351®) (2017) Gene therapy TR-targeted liposomes encapsulating a I/II Pediatric solid tumors, Intravenous NCT02354547, NCT02340117, p53-encoding plasmid (SGT-53®) glioblastoma, pancreas NCT02340156 RNA Lipid nanoparticles encapsulating interfering I/II Solid tumors, Edwing’s Intravenous [247] interference RNAs sarcoma, liver, AML TME Various NPs for CAFs, TAMs, ECs, ECM suppression Preclinical Various cancer models Mostly intravenous [291] modification or normalization Immunotherapy Vectorization of various immunomodulators Preclinical Various cancer models Mostly intravenous [291] Inorganic Hyperthermia Minosilane-coated iron oxide nanoparticles Approved Glioblastoma Intratumoral [307] nanoparticles (Nanotherm®) (2010) Radiotherapy Hafnium oxide nanoparticles (NBTXR3®/Hensify®) Approved Squamous cell carcinoma Intratumoral [137] (2019) RNA siRNAs adsorbed on gold nanoparticles I Glioblastoma Intravenous [247] interference Bacterial minicells Chemotherapy EGFR-targeted, doxorubicin-loaded minicells I/II Glioblastoma Intravenous [63] RNA EGFR-targeted minicells containing a miRNA I Mesothelioma, NSCLC Intravenous [64] interference mimics cocktail Extracellular vesicles Chemotherapy Tumor-derived microvesicles packaging II Lung cancer Intravenous NCT02657460 methotrexate Gene therapy Tumor-derived exosomes loaded with Proof-of- Heterotopic ovarian cancer model Intravenous [308] CRISPR-Cas9 against PARP1 concept RNA MSC-derived exosomes loaded with I Metastatic prostate cancer Intravenous NCT03608631 interference anti-KrasG12D siRNAs Virus-like particles Chemotherapy Tobacco Mosaic Virus carrying phenanthriplatin Preclinical Heterotopic breast cancer model Intravenous [73] Gene therapy TP53-encoding non-replicating adenovirus Diverse Solid cancers Mostly intratumoral [208] M13 phage encoding HSV-TK Preclinical Orthotopic glioblastoma model Intravenous [309] RNA delivery MS2-derived VLPs carrying siRNAs Proof-of- Hepatocellular carcinoma cell line NA [310] concept Briolay et al. Molecular Cancer (2021) 20:55 Page 11 of 24 Table 3 Representative examples of the advancement of nanovectors in cancer therapy (Continued) Nanovector Therapy Drug administration Phase Cancer types Route of References family administration Oncolytic viruses Chemotherapy HSV-TK-encoding adenovirus II Triple-negative breast cancer, NSCLC, Intratumoral NCT03004183, [311] prostate HSV-TK-encoding vaccinia virus II Solid tumors Intravenous NCT04226066 Radiotherapy NIS-encoding measles virus II Multiple myeloma Intravenous NCT02192775 II Ovarian, fallopian and peritoneal Intraperitoneal NCT02364713 cancers Gene therapy TP53-encoding replicating viruses Preclinical Many solid cancers models Intravenous / [208] Intratumoral RNA Oncogene silencing with small Preclinical Many solid cancer models NA [312, 313] interference RNAs-encoding Adenovirus and HSV TME Hyaluronidase-expressing adenovirus Preclinical Orthotopic glioblastoma model Intratumoral [134] modification Immunotherapy GM-CSF-encoding herpes simplex virus Approved Melanoma Intratumoral [94, 97] (Talimogene laherparepvec) (2015) AML acute myeloid leukemia, CAF cancer-associated fibroblast, EC endothelial cell, ECM extracellular matrix, EGFR epidermal growth factor receptor, HSV-TK herpesvirus thymidine kinase, NP nanoparticle, NSCLC non- small cell lung carcinoma, TAM tumor-associated macrophage, TR transferrin receptor, VLP virus-like particle Briolay et al. Molecular Cancer (2021) 20:55 Page 12 of 24 mostly relied on passive targeting due to destabilized and limit efflux, thereby enhancing drug concentration in tumor vasculature and the resultant EPR effect. Based tumor cells. They can also carry several drugs at the same on a similar idea, the natural tumor distribution of fila- time to strike cancer cells on different fronts simultan- mentous VLPs [77, 149] can also be exploited for this eously and prevent therapeutic escape [157]. Such strat- purpose; PEGylated Potato Virus X (PVX) VLPs pas- egies can combine several chemotherapies [152]or sively loaded with doxorubicin were indeed shown to different types of treatments such as a combination of a elicit a better control of breast cancer xenografts in im- chemotherapeutic drug with a siRNA [158]. Doxorubicin- munodeficient mice than doxorubicin alone [140]. How- coated, multifunctional mesoporous silica nanoparticles ever, a combination of PVX and doxorubicin was more containing a siRNA against the P-glycoprotein (Pgp) drug effective than doxorubicin-loaded PVX in an immuno- exporter showed targeted Pgp knockdown and a synergis- competent melanoma model [141], suggesting that VLPs tic inhibition of resistant breast tumor growth in preclin- elicit an adjuvant anti-tumor immune response that par- ical models [159]. A similar approach used sequentially (i) ticipates in the therapeutic effect and pleading for the CD33- or EGFR-targeted bacterial minicells containing a use of immunocompetent animal models for future plasmid coding for shRNAs against MDR pumps and (ii) evaluations. chemotherapies [160]; mice bearing drug-resistant colo- Current studies mostly focus on actively targeted rectal, breast or uterine tumors were efficiently treated nanodrug formulations to enhance interactions of the without toxicity as a thousand-fold less drug and shRNA nanoparticles with malignant cells after having reached were used compared to conventional systemic treatment. the TME [23, 24, 27]. Several strategies have demon- Another way to circumvent tumor resistance is to use strated increased drug concentration in tumors and highly cytotoxic compounds – such as the PNU-159682 enhanced therapeutic efficacy compared with the metabolite [161] – that cannot be injected systemically be- corresponding free molecules or untargeted nanovectors cause of their high toxicity. Systemic vectorization of this [23, 150]. In a preclinical study, paclitaxel-loaded nano- drug in EGFR-targeted bacterial minicells showed signifi- capsules constituted of a lipid core surrounded by a cant tumor reduction and immune activation with no side surfactant were targeted to the altered tumor vascular effects in immunocompetent breast and colorectal murine endothelium with an iRGD peptide [151]. The authors models but also lung and colorectal human cancer demonstrated that the targeted nanoparticles concen- xenografts [162]. trated in hepatic tumors, induced specific cytotoxicity and were better tolerated than non-targeted nanoparti- Exploiting intrinsic physical properties cles. Another recent study showed that hybrid solid-lipid Some chemically engineered nanoparticle families have nanoparticles decorated with folic acid can significantly intrinsic physical properties that make them suitable for increase the concentration of carboplatin and paclitaxel combined therapies. As such, gold nanoparticles can be in tumors cells in a murine cervical cancer model [152]. used for photothermal therapy, which consists in a local EGFR-targeted, doxorubicin-containing bacterial mini- vibrational heat generation through the absorption of cells were demonstrated to rapidly locate in spontaneous specific wavelengths of light [163]. Super Paramagnetic gliomas in dogs, a tumor usually difficult to reach be- Iron Nanoparticles (SPIONs) on the other hand can be cause of the blood-brain barrier [60]. Another approach used for hyperthermia, a local heat generation under a for active tumor delivery is to target the hypoxic center magnetic field [164]. Those two phenomena have dem- and acidic microenvironment of tumors, in particular onstrated a moderate therapeutic efficacy on their own using the pH (low) insertion peptide (pHLIP) [153]. An but can sensitize cancer cells to chemotherapies loaded example for this strategy is the use of doxorubicin- in the same nanoparticles [165]. Indeed, hyperthermia loaded bacterial minicells with a pHLIP added to their and photothermia inhibit the repair of DNA lesions (e.g. membrane, which successfully invaded the necrotic and double-strand breaks) generated by chemotherapy or hypoxic regions of orthotopic murine breast cancers and radiotherapy [166]. Several clinical trials involving the achieved a significant tumor reduction compared to both use of hyperthermia as adjuvant for chemotherapy are free drug and untargeted minicells [154]. ongoing [167]. An example is the use of a near-infrared- responsive polypeptide nanocomposites charged with Fighting resistance doxorubicin and capable of heat generation and heat- Cancer cells commonly develop resistance against sensitive nitric oxide (NO) gas delivery [168]. This chemotherapies, for instance by acquiring a multidrug combination of photothermia, NO gas therapy and resistance (MDR) phenotype. This can result from the chemotherapy achieved complete breast tumor regres- expression of ATP-dependent transporters that promote sion in mice after a single near-infrared irradiation. the efflux of drugs outside the cell to escape death induc- Hyperthermia can also be used to release chemothera- tion [155, 156]. Nanovectors enable drug immobilization peutics enclosed in hybrid delivery systems constituted Briolay et al. Molecular Cancer (2021) 20:55 Page 13 of 24 of nanoparticles associated with thermosensitive improved treatment efficacy. However, the clinical trans- molecules [169]. Regarding epigenetic modulation, some lation of these metallic nanoparticles remains challen- studies suggest that metallic and silica nanoparticles ging because of both their tendency to aggregate after could directly induce modifications of DNA methylation systemic injection and their long-term toxicity due to or of histone acetylation and disrupt miRNA expression liver accumulation. An alternative are chemical ROS- [170, 171], but the significance of these modifications in generating photosensitizers that can be coupled to a the context of cancer treatment is still to be investigated. wide variety of biocompatible nanoparticles for PDT The nanovectorization of chemotherapeutic drugs has [177, 178]. Interestingly, some chemical radiosensitizers been historically dominated by the use of organic are also able to self-assemble to generate nanostructures nanoparticles (Table 2), supported by their unmatched by themselves [179]. Upconverting nanoparticles were diversity of structures and compositions (Fig. 2). This recently modified to assemble with a photosensitizer led to different clinical successes resulting in several in vivo by click chemistry after systemic injection [180]. drug approvals (Table 3). However, the more recent ad- These nanoparticles are able to convert low energy near- vances in vesicular nanovectors (e.g. bacterial minicells, infrared light into high energy photons that activate the EVs), provide new solutions with enhanced biocompati- photosensitizer to generate ROS and achieved inhibition bility (Table 1) that may advantageously replace syn- of tumor growth in an ectopic breast cancer model. A thetic nanoparticles in some clinical contexts. Studies on recent study used EVs purified from mouse blood and VLPs are at an earlier stage of development but also surface-loaded with the photosensitizer protoporphyrin demonstrated interesting properties in preclinical experi- IX (PplX) in a two-stage irradiation protocol to ments. In the end, hybrid vectorization systems incorp- efficiently deliver PplX and induce apoptosis by PDT in orating both synthetic and biological moieties may a breast tumor model [181]. The porphyrin photosensi- constitute a rational compromise between efficacy, tizer has also been effectively vectorized with M13 fila- biocompatibility and standardized manufacturing even if mentous phage VLPs retargeted to mammary cancer complex designs may generate additional difficulties for cells by a specific peptide displayed on the pVIII coat clinical development. protein and demonstrated efficient cancer cell targeting and sensitization to PDT [182]. The lack of oxygen in Radiotherapy the tumor hypoxic core can lead to radioresistance, Half the cancer patients receive radiotherapy – which which can be bypassed by developing nanoparticles with exploits the low resistance of tumor cells to radiation- O -elevating abilities or nano-radiosensitizers with induced DNA damages – during their course of treat- diminished oxygen dependence [183]. As an example, ment [172]. Overexposure of healthy cells to radiations mesoporous manganese dioxide nanoparticles are able leads to radiotherapy-related toxicities that could be to catalyze O production to actively reverse hypoxia in partially addressed using appropriate vectorization tumors. These nanoparticles were loaded with the pho- strategies. For external-beam radiotherapy [173] – or for tosensitizer acridin orange and exhibited enhanced related photodynamic therapy (PDT) that uses non- radiotherapy efficacy both in vitro and in vivo in a lung ionizing wavelengths [163] – nanovectors can sensitize cancer xenograft model [184]. Hypoxia-reverting lipo- tumors to radiations. For internal radiotherapy, nanomedi- somes [185], macromolecular nanoassemblies [186, 187] cine is an elegant solution to deliver specifically radioele- and other types of nanoparticles [177] have also been ments to tumors and an alternative to the use of radiolabeled used for their photosensitizing properties. antibodies in radioimmunotherapy approaches [174]. The radiosensitizer family also encompasses all mole- cules able to enhance tumor cell sensitivity to radiation a. Radiosensitization effects by interfering with essential cellular pathways like DNA repair, apoptosis induction or cell cycle progres- Radiations not only cause direct damages to biomole- sion. As such, chemotherapeutics are used as radiosensi- cules but also generate reactive oxygen species (ROS). tizers at the clinical level [175] and their loading on This phenomenon can be enhanced in tumors by the chemically engineered nanoparticles have demonstrated vectorization of radiosensitizing molecules that increase radiosensitizing effects [185, 188, 189]. As for chemo- either ROS production in response to ionizing beams or therapy, SPIONs and gold nanoparticles alone or within malignant cell sensitivity to both direct and indirect a bigger organic nanoparticle can also mediate tumor radiation effects [175]. Gold nanoparticles (AuNPs) are radiosensitization through inhibition of DNA repair well-characterized for their radiosensitizing properties mechanisms by hyperthermia or photothermia, respect- [176]; their concentration in tumors increases the dose ively [166]. DNA viruses are capable of impairing the delivered locally during radiotherapy, resulting in ROS DNA damage response [190] and some OVs (e.g. adeno- production, DNA repair machinery impairment and viridae) naturally downregulate key proteins involved in Briolay et al. Molecular Cancer (2021) 20:55 Page 14 of 24 the response to radiation-induced DNA damages [191], Delivery of nucleic acids which makes them intrinsically radiosensitizing [192]. Malignant transformation results from gene alterations SiRNA-mediated gene silencing is another strategy to (e.g. deletions, amplifications, mutations, translocations, target genes involved in the cellular response to ionizing epigenetic or viral dysregulations) that displace the equi- radiations [175]. As discussed below, OVs and VLPs are librium between oncogene and tumor-suppressor gene useful tools for such small RNA vectorization, an ex- expression. These alterations can be corrected or com- ample being an adenovirus encoding a shRNA against pensated using nucleic acids (DNA or RNA) for gene the DNA-dependent protein kinase DNA damage editing (over-expression or knock-out), direct induction response protein for local enhancement of radiotherapy of cell death by expression of toxic genes or by modulat- in a human colorectal cancer xenograft model [193]. ing gene expression. As free nucleic acids are rapidly degraded in the bloodstream and do not cross cell b. Internal radiotherapy membranes, clinical translation of cancer gene therapy requires proper vectorization [208]. Viruses are par- Radionuclides have been vectorized for several years ticularly suited for this as they are naturally designed with various nanovectors like VLPs [194–196], EVs to deliver genes in targeted cells (Table 2). Transgenic [197], nanoparticles [198, 199] or an oncolytic adeno- viruses are also relatively simple to generate and they virus [200] for cancer imaging, but for VLPs or EVs this ensure a high level of transgene expression. Many has yet to be studied in therapeutic protocols. High- studies were conducted with retrovirus-like particles energy, short-range alpha-emitters have been conjugated (RLPs) [209], non-replicative adenoviruses [210]and to various types of chemically engineered nanoparticles AAVs [211], whereas other VLPs used for both their with good therapeutic results but a large majority of capacity to package DNA and their easy retargeting radionuclides currently used in cancer therapy are low- achieved lower transduction efficacy [68, 82, 212]. energy beta-emitters with a longer path length [201]. Despite several limitations – the main one being the Iodine 131 ( [143]I) is the most common nanoparticle- cytoplasmic delivery of cargos initially addressed to coupled radionuclide reported in the literature. Recent the nucleus – nanoparticles (mainly lipid-based) have examples include PEGylated, nuclei-targeted [143]I- been extensively used for nucleic acid delivery [213– AuNPs tested in a colorectal cancer model [202] and 215]. Some strategies are developed to increase [143]I-labeled, human serum albumin-bound manganese nanoparticle-mediated gene expression in tumor cells dioxide nanoparticles that were capable of significantly [216], for instance by using nuclear localization sig- inhibiting tumor growth in a breast cancer model with a nals (NLS) or by vectorizing messenger RNAs [217]. potentiating effect of MnO on radiotherapy efficacy [203]. In another study, treatment with PEGylated lipo- Gene therapy somes enclosing an [143]I-albumin core led to subcuta- The most frequent genetic alterations in cancer being neous breast tumor shrinkage when co-administered p53 mutations, most gene therapies consist in vectoriz- either with liposomes containing a photosensitizer or ing a wild-type TP53. Restoring wild-type p53 functions with an anti-PD-L1 antibody [204]. In a very different triggers cell death specifically in highly-dividing tumor strategy, OVs coding for the human sodium-iodine sym- cells exhibiting genome instability. An example of a porter (NIS) have been used to enhance the specific in- nanovector exploiting this mechanism is Gendicin, a take of [143]I in OV-infected tumor cells [99, 205–207]; p53-encoding adenoviral vector that was the first-in-class OV-NIS are injected several days before [143]I and in- gene therapy treatment for head and neck cancer directly mediate the vectorization of the radioelement to approved by the China Food and Drug Administration in tumors neo-expressing NIS. 2003 [218]. While many years of clinical use demonstrated As for chemotherapy, the different subfamilies of its safety, its efficacy remains limited. However, the co- nanoparticles have been massively investigated to im- vectorization of other tumor suppressors (e.g. ING4, prove the efficacy of radiotherapy, but the low biocom- PTEN) in the same vector demonstrated synergistic patibility and biodegradability of inorganic nanoparticles efficacy [83]. The enhanced vectorization potential and called for the development of alternatives. Successful de- intrinsic tumor cytotoxicity of OVs were also exploited to livery of radiosensitizing molecules was achieved with transiently express tumor suppressors at high levels but organic nanoparticles and bio-inspired vectors such as still lack clinical assessment [129]. Regarding nanoparti- EVs, while engineered VLPs can be chemically coupled cles, liposomes containing p53-encoding plasmids are to radionuclides. Viruses and other bio-derived vectors being evaluated against different types of solid cancers are also expected to define original approaches to exploit [219, 220], including in phase I/II clinical trials precise biological mechanisms that are involved for (NCT02354547, NCT02340156, NCT02340117). instance in the cellular response to radiations. Briolay et al. Molecular Cancer (2021) 20:55 Page 15 of 24 Other studies focus on cancer gene editing to dis- another example, HSV-TK plasmid-bearing macromolecular able key oncogenes. An oncolytic myxoma virus car- nanoassemblies demonstrated a significant therapeutic effect rying a CRISPR cassette targeting the NRAS oncogene against invasive orthotopic human glioblastoma multiforme demonstrated efficient gene editing in vivo along with in mice [238]. prolonged survival in a xenograft model of rhabdo- Cytotoxic gene therapy on the other hand consists in myosarcoma [221]. Similarly, a CRISPR-Cas12a-carry- delivering a cell death-triggering gene to tumors. To ing oncolytic adenovirus efficiently edited EGFR avoid off-target effects, the expression is generally in vivo specifically in xenografted lung adenocarcin- controlled by a cancer- or tissue-specific promoter [229]. oma cells [222]. Transgene-free retroviral VLPs loaded The main focus has been on tumor necrosis factor with Cas9-sgRNA ribonucleoproteins (“nanoblades”) (TNF)-related apoptosis-inducing ligand (TRAIL)-based that demonstrated in vivo genome editing capacity cancer therapy, TNF-α and TRAIL being major media- [223] and can be pseudotyped to modulate their cell tors of death receptor-mediated apoptosis. Delivery of tropism may also have interesting applications for TNF-α- or TRAIL-encoding genes for secretion of the cancer therapy. Alternatively, lipid-based nanoparticles cognate proteins by tumor cells was reported with OVs [224] and macromolecular nanoassemblies [225, 226] [239], VLPs [82, 240] or nanoparticles [241] with have been successfully used to deliver CRISPR-Cas9- evidence of a bystander effect. Interestingly, displaying encoding plasmids for oncogene edition. As an ex- the TRAIL protein on the surface of nanovectors has ample, tumor-targeted macromolecular nanoassem- also demonstrated efficient TRAIL-mediated cell death blies decorated with a NLS-containing peptide induction of circulating tumor cells in different studies specifically delivered a CRISPR-Cas9 plasmid to the [242–244]. An alternative is the use of inducible suicide nuclei of lung cancer cells in vitro and efficiently genes, an elegant example being the vectorization by knocked out the Catenin beta-1 gene [227]. Neverthe- adenoviral vectors [245] and AAVs [246] of the less, the dysregulation of tumor suppressor genes in AP20187-dependent inducible version of caspase 9, cancer being frequently post-transcriptomic, this may activated after AP20187 treatment. Another example is limit the actual efficacy of gene editing. In addition, the AAV vectorization of a CRISPR system targeting gene delivery mostly impacts the cells receiving the telomeres to induce tumor cell death [211]. Several transgene and will have limited bystander effects. pathogen-derived toxins have also been studied as cell Other approaches may thus be more adapted to ad- death inducers for cancer cytotoxic gene therapy. An dress the heterogeneity of malignant diseases. example is the tumor-specific, apoptosis-triggering viral protein apoptin that was encoded by lambda phage VLPs Induction of cell death [247] or OVs [248] and induced significant tumor Gene therapies for triggering specific tumor cell death reduction in breast and lung cancer models, respectively. include Gene-Directed Enzyme/Prodrug Therapy (GDEP A recent innovative study described the design of T) [228] and cytotoxic gene therapy [229, 230]. GDEPT macromolecular nanoassemblies loaded with a light- involves the tumor delivery of a transgene encoding an switchable transgene coding for the diphtheria toxin A enzyme able to convert a non-toxic prodrug into a inducible by blue laser light, a protocol that improved cytotoxic drug, the latter exerting its activity against the survival in a melanoma model [249]. In parallel to these modified tumor cells and its surrounding environment. gene delivery approaches, several groups also vectorized Such transgenes include the herpes simplex virus thymi- the different toxins as proteins to trigger selective cancer dine kinase (HSV-TK) gene, converting ganciclovir into cell death with nanoparticles [250, 251], VLPs [131] and ganciclovir-triphosphate and inhibiting DNA elongation bacterial minicells [252]. [231], and the cytidine deaminase that converts 5- fluorocytosine into 5-fluorouracile [228]. VLPs (e.g. ade- Modulation of gene expression noviruses) are the most suitable and the more frequently Cellular pathways and gene expression can be precisely used nanovectors for suicide gene therapy due to their modulated by RNA interference (RNAi). This involves high gene transfer potential [232, 233]. For OVs, HSV de different types of small RNAs such as microRNAs (miR- facto expresses HSV-TK [234] but this transgene has NAs) and small interfering RNAs (siRNAs) that interact also been vectorized by other viruses [235, 236]. Lipo- with specific target mRNAs and stimulate their degrad- somes were also used to actively deliver a mRNA or a ation or the inhibition of their translation [253]. The plasmid coding for the HSV-TK protein in a lung cancer targeted inhibition of oncogenic mRNAs or miRNAs mouse model [237]. The authors showed that both attracts attention but effective delivery of small RNAs mRNA- and plasmid-carrying liposomes can mediate a for cancer treatment requires appropriate vectorization, significant inhibition of tumor growth following ganciclovir in particular to reduce their degradation by nucleases. injection with a superiority of the mRNA formulation. In To date, siRNAs and miRNAs have been mostly vectorized Briolay et al. Molecular Cancer (2021) 20:55 Page 16 of 24 by chemically engineered nanoparticles, in particular delivery of nucleic acids for cancer therapy (Table 3). liposomes as extensively reviewed elsewhere [213, 254]. On the one hand, gene therapy approaches are domi- The safety of siRNA vectorization by liposomes – for in- nated by viral vectors (e.g. VLPs, OVs) (Table 2) due to stance against genes coding for the Ephrin type-A receptor their natural abilities to deliver to the nuclear compart- 2 or B-cell lymphoma 2 (BCL-2) – is under evaluation in ment therapeutic transgenes that will be efficiently several ongoing clinical trials [125, 255]. SiRNAs directed expressed. On the other hand, the efficient delivery of against oncogenes (e.g. MYC, BRAF, BCL-2) have also been RNA molecules has been demonstrated for almost all transported with macromolecular nanoassemblies or types of nanovectors described in this review. EVs natur- inorganic nanoparticles [256] and, more recently, an anti- ally transport small RNAs and present a high biocompati- survivin siRNA was efficiently vectorized with dendrimers bility, but lipid-based nanoparticles, bacterial minicells that were further entrapped in tumor-derived EVs for treat- and viruses are also adapted to such vectorization. With ing mice bearing prostate carcinoma [54]. the expected boom of cancer gene therapies in the next MiRNAs are naturally transported by EVs throughout few years, upcoming clinical studies will provide critical the organism to modulate gene expression in neighboring data to determine which vectors are the best compromise or distant cells, both in physiological and pathological when considering efficient nucleic acid delivery, biocom- conditions [39]. This process was harnessed in several patibility and ultimately clinical efficacy. studies to deliver miRNAs or anti-miRNAs to cancer cells [47]. Human fibroblast-derived exosomes containing Tumor microenvironment modulation & immunotherapy G12D Kras -targeted siRNAs were thus shown to mediate a In recent years, cancer treatment has rapidly evolved from better inhibition of tumor growth compared to liposomes directly targeting malignant cells to treating the TME as a in pancreatic cancer models [257]; this difference of whole [267, 268]. The stromal and immune compartments efficacy was attributed to the lower immunogenicity and that constitute this complex environment support cancer decreased clearance of exosomes. Similarly, mesenchymal growth, maintenance, resistance and recurrence and can stem cell-derived EVs were used to deliver several tumor- be targeted for destruction or reprogramming. New tech- suppressing miRNAs to malignant cells by exploiting both nologies like single-cell profiling continuously provide a their alleged natural tropism for tumors and immune better understanding of this tumor heterogeneity and help evasion abilities [254, 258, 259]. Another example is the both deciphering the intertwined mechanisms involved use of natural killer cell-derived exosomes loaded with a and developing new rationale-based therapies to target Let-7a miRNA-coupled dendrimer that were efficiently them. This is perfectly illustrated by the breakthrough of delivered in vivo to neuroblastoma cells [260]. However, cancer immunotherapies that use either immune activat- the natural miRNA content of EVs may mediate ing signals (e.g. cytokines, agonist antibodies) or inhibitors unwanted effects in tumors and preclude clinical applica- of immunomodulating cues (e.g. immune checkpoint in- tions; one should carefully choose the EV donor cell type hibitors). Nevertheless, limiting off-target toxicities and or opt for alternatives such as artificial exosome–mimetic moderate efficacies call for improved vectorization to fur- nanoplatforms that simulate natural cell-derived exosomes ther refine these approaches. Nanovectors can modulate but with a controlled composition [261]. Micro-organism- the pharmacokinetics of immunotherapies, deliver lo- derived nanovectors are also a suitable alternative to cally combination therapies and sometimes display an vectorize miRNAs. In a phase I clinical trial, patients with intrinsic therapeutic potential [269, 270](Table 2). malignant pleural mesothelioma were treated intraven- ously with EGFR-targeted bacterial minicells containing a. Removing life support miRNA mimics [64]; the study concluded to treatment safety associated with a disease control rate of 65%, but Cancer-associated fibroblasts (CAFs) and tumor- the precise intake mechanism is still to be characterized. associated macrophages (TAMs) secrete immunomodula- MS2 bacteriophage VLPs can be loaded with siRNAs or tory cytokines, growth factors and pro-angiogenic molecules long non-coding RNAs and efficiently deliver their cargo that participate in tumor maintenance [267, 268]. A valid in targeted cells [131, 262], whereas RLPs can be used for strategy would consist in eliminating these stromal cells, for stable interfering RNA expression in cancer cells [263, instance by using targeted nanoparticles to specifically 264]. Successful in vivo vectorization of siRNAs against deliver chemotherapies and/or photosensitizers to the epigenetic regulator HDAC1 [265] or the viral onco- CAFs [271–274] or bisphosphonates and other cyto- gene E6 [266] was also achieved with OVs and was associ- toxic molecules to TAMs [269, 275]. In these ap- ated with prolonged survival in models of metastatic proaches, nanoparticles are actively targeted to CAFs melanoma or cervical cancer, respectively. and TAMs, mostly with FAP- or αSMA-specific mole- To conclude, all nanovector families are investigated cules, or with mannose moieties, respectively. OVs have either in preclinical studies or clinical trials for the also been used for anti-CAF bispecific T cell engagers Briolay et al. Molecular Cancer (2021) 20:55 Page 17 of 24 (BiTEs) delivery to selectively mediate CAF death via T promotes T cell infiltration in the infected tumors and cell activation [276, 277]. Interestingly, the use of OVs, could improve the efficacy of immune checkpoint inhibi- which infect malignant cells and replicate in the TME, tors [293]. The vectorization of immunomodulating allows for continuous local production of anti-CAF transgenes with OVs or VLPs turns cancer cells into BiTEs by infected tumor cells. OVs can also be therapeutic factories within the TME [86, 294] as shown addressed directly to CAFs by exploiting CAF-specific with immune checkpoint inhibitors encoded from engi- promoters [278] or receptors [279] as shown with an neered viruses [295, 296]. This changes the pharmacokinet- adenovirus and measles virus, respectively. ics of immunotherapies and enables the use of potent Endothelial cells are other important actors of the immune activators (e.g. trimerized CD137L, IL-12) that are TME as they ensure nutrient and oxygen supply to toxic or even lethal when used systematically without growing tumors. To induce tumor cell death, the tumor proper vectorization. It also facilitates combinations, for ex- vasculature can thus be impaired by vectorizing anti- ample by inserting into large DNA virus genomes multiple angiogenics, mostly VEGF inhibitors or anti-VEGF siR- immunotherapeutic transgenes (e.g IL-12 + anti-PD-L1) NAs. Those have been developed as single agents over targeting different immune mechanisms for synergistic the last two decades but showed major side effects, such effects with no additional toxicity [296–298]. as hemorrhages or thromboses [280]. Anti-angiogenics To vectorize immunotherapies targeting the TME have been vectorized efficiently with nanoparticles [280], [126], nanoparticles are generally combined with ICD in- bacterial minicells [61] and OVs [281], either by active ducers (e.g. hyperthermia) on the same vector in order targeting to the tumor endothelium (e.g. iRGD peptide) to stimulate immune cell recruitment and activation or by relying on the EPR effect. As an example, untar- [269, 299–301]. Contrary to transgene vectorization by geted liposomes were used to co-deliver an anti-VEGF OVs, nanoparticles usually transport proteins, which siRNA and etoposide and caused a significant inhibition does not allow spatial and temporal treatment amplifica- of tumor growth in an orthotopic non-small cell lung tion. Nevertheless, inhibitors of IL-10, TGF-β, indolea- cancer model compared to the combinations of either mine 2,3-dioxygenase immunosuppressive molecules free drugs or the separate liposomal formulations [282]. [273], TLR agonists [302–304] or pro-inflammatory cy- Similarly, the anti-VEGF antibody bevacizumab and er- tokines (e.g. IL-2, IL-15, TNF-α, IFN-γ)[15, 305–308] lotinib were co-vectorized in pH-sensitive lipid-polymer have been successfully addressed to the TME in preclin- hybrid nanoparticles and achieved significant inhibition ical models using different types of nanoparticles [275, of non-small cell lung cancer growth in mice [283]. 309]. Those have also been used to vectorize anti-OX40 [310] and anti-CD137 [311] agonist antibodies or anti- b. Reprogramming the environment PD-1 [310] and anti-PD-L1 [312] antagonist antibodies in mice to enable efficient T cell activation in the TME Normalizing the TME by modifying the phenotypes [270, 299]. In an elegant study, a tritherapy consisting in and functions of its cellular components has become a an immune checkpoint inhibitor (i.e. anti-PD-L1) and therapeutic strategy to beat cancer [284]. Since repro- two T cell activators (i.e. anti-CD3 and anti-CD28) con- gramming myeloid cells toward anti-tumor phenotypes jugated on the same nanoparticle was shown to augment can promote favorable immune responses, several strat- the therapeutic index of the combination against murine egies aim at re-educating TAMs into pro-inflammatory breast and colorectal cancers [313], which illustrates the M1-like macrophages [285]. This can be achieved using versatility of nanoparticles in this context. pro-inflammatory cytokines (e.g. IL-12), miRNAs or Recent clinical advances in cancer immunotherapy and TLR agonists which systemic delivery was shown to be TME reprogramming are yet to be enhanced efficiently highly toxic unless vectorized by nanoparticles [285–288] by appropriate vectorization approaches. Viruses display or VLPs [289]. Other types of immunosuppressive cell natural abilities (e.g. transgene transport and expression, types such as myeloid-derived suppressor cells or regulatory intrinsic immunogenicity) for this, with OVs also T cells can also be targeted by engineered nanoparticles exhibiting replication and oncolysis properties that can [275]and OVs[290]. further improve their therapeutic efficacy. The develop- OVs display intrinsic properties (e.g. induction of ment of clinical-grade viruses may be however challen- immunogenic tumor cell death (ICD), release of ging and organic nanoparticles, which are investigated in damage- and pathogen-associated molecular patterns) numerous preclinical studies to deliver immunomodulat- that make them perfectly suited for such reprogramming ing proteins to tumors, offer good alternatives when approaches in cancer immunotherapy. Clinical trials re- considering their multiple engineering possibilities. The ported that OV-induced ICD can be sufficient to induce most efficient designs are still to be identified in clinical an abscopal anti-cancer immune response and lead to studies but advances in vaccination strategies using tumor eradication [94, 291, 292]. OV infection also nanoparticles, for instance regarding Covid-19, may Briolay et al. Molecular Cancer (2021) 20:55 Page 18 of 24 accelerate these developments. As for VLPs, EVs and increasing complexity of synthetic nanoparticles, in par- bacterial minicells, their ability to vectorize biomolecules ticular for combination therapies, will necessitate radical to modulate the TME has been demonstrated but optimization of production methods. For the bio- clinical evidence is still missing. inspired nanovectors, the issues associated with the cost and the technical difficulties of large-scale productions Conclusion still hinder their wider development. Moreover, the The last three decades have seen the discovery of a tre- nanovectorization of anticancer therapeutics also lacks mendous number of new anti-cancer molecules selected solid pharmacological and toxicological studies; im- for their tumor-specific cytotoxicity and, more recently, provements and solutions may come from advances in for their ability to alter the TME. However, a large ma- parallel fields such as recombinant protein production, jority of the molecules identified on the bench fail in the conventional gene therapy or regenerative medicine. clinic because of a poor efficacy/safety ratio after sys- These problems highlight the importance of integrating temic administration. Despite personalized combinations the issue of therapeutic delivery in the process of drug to strike tumors on different fronts, resistance and development and call for a closer relationship with the toxicities are still major issues that limit many thera- field of drug discovery. As such, acknowledging the di- peutic applications. The advent of nanotechnologies versity of available delivery systems may act as a lever in opened an entirely novel area of research around the drug discovery and reveal numerous therapeutic mole- nanovectorization of anti-tumor therapeutics to both in- cules that would have been rejected because of alleged crease treatment efficacy and reduce associated toxicities unfavorable properties (e.g. poor solubility, high tox- by improving dramatically the specificity of tumor tar- icity), thereby expanding the therapeutic arsenal against geting. Chemically engineered nanoparticles – highly cancer. adaptable and for some relatively easy to manufacture – Abbreviations were the first to enter the clinic but with the current AAV: adeno-associated virus; AuNP: gold nanoparticle; CAF: cancer-associated trend to improve the biocompatibility and to exploit pre- fibroblast; ECM: extracellular matrix; EGFR: epidermal growth factor receptor; REPR: enhanced permeability and retention; EV: extracellular vesicle; GDEP cise biological mechanisms, bio-inspired nanovectors T: gene-directed enzyme/prodrug therapy; MDR: multidrug resistance; (e.g. VLPs, bacterial minicells, EVs, OVs) are now rapidly NIS: sodium/iodide symporter; NO: nitric oxide; OV: oncolytic virus; gaining interest. These different families of nanovectors PAA: polyacrylic acid; PDT: photodynamic therapy; PEG: polyethylene glycol; pHLIP: pH (low) insertion peptide; RLP: retrovirus-like particle; RNAi: RNA allow the vectorization of almost all anti-cancer thera- interference; ROS: reactive oxygen species; SPION: super paramagnetic iron peutics, including chemical drugs, radio-elements, nu- nanoparticle; TAM: tumor-associated macrophage; TME: tumor cleic acids, toxins and immunotherapies (Table 2). To microenvironment; VLP: virus-like particle this day, chemotherapies, radioelements and molecules Acknowledgements that sensitize tumors to radiotherapies have been more We thank Pr Elena Ishow, Ugo Hirigoyen and Thomas Ogor for proofreading efficiently vectorized with synthetic nanoparticles but of the manuscript. All figures were created with promising results have also been obtained with bacterial minicells and VLPs. By their very nature, viral vectors Authors’ contributions are the most suitable for gene therapy and nucleic acid TB, TP & NB initiated the study. TB, TP, MF, NN & NB performed the scientific vectorization, yet lipid-based nanoparticles have been ex- literature search and designed the review structure. TB, TP & NB wrote the manuscript. TB, TP & MF designed the tables and figures. CB & NB tensively studied for these applications and may be more supervised, helped to revise and edit the manuscript. All authors read and adapted – along with EVs or even bacterial minicells – approved the final manuscript. to the delivery of small RNAs. Finally, nanoparticles can Funding efficiently vectorize immunomodulatory proteins but This work was supported by grants from La Ligue Contre le Cancer Grand OVs are becoming a new standard thanks to their intrin- Ouest, la Région Pays de la Loire, l’Université de Nantes and l’Agence sic immunogenic properties and their ability to sustain Nationale de la Recherche (ANR-20-CE18-0009-01). local expression of immunomodulatory transgenes. Availability of data and materials The field of nanovectorization is overly active and has Not applicable. already provided important advances for cancer therapy, with clinical approvals for several simple nanoformula- Declarations tions (Table 3). Current developments however focus on Ethics approval and consent to participate more complex structures including biological or bio- Not applicable. inspired objects. 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Delivery of cancer therapies by synthetic and bio-inspired nanovectors

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