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Tailoring the Inherent Properties of Biobased Nanoparticles for Nanomedicine
Abstract
Biobased nanoparticles are at the leading edge of the rapidly developing field of nanomedicine and biotherapeutics. Their unique size, shape, and biophysical properties make them attractive tools for biomedical research, including vaccination, targeted drug delivery, and immune therapy. These nanoparticles are engineered to present native cell receptors and proteins on their surfaces, providing a biomimicking camouflage for therapeutic cargo to evade rapid degradation, immune rejection, inflammation, and clearance. Despite showing promising clinical relevance, commercial implementation of these biobased nanoparticles is yet to be fully realized. In this perspective, we discuss advanced biobased nanoparticle designs used in medical applications, such as cell membrane nanoparticles, exosomes, and synthetic lipid-derived nanoparticles, and highlight their benefits and potential challenges. Moreover, we critically assess the future of preparing such particles using artificial intelligence and machine learning. These advanced computational tools will be able to predict the functional composition and behavior of the proteins and cell receptors present on the nanoparticle surfaces. With more advancement in designing new biobased nanoparticles, this field of research could play a key role in dictating the future rational design of drug transporters, thereby ultimately improving overall therapeutic outcomes.
... 12 These nanoparticle-based drug carriers exhibit notable advantages such as extended shelf life, leading to increased stability, and can facilitate a wide range of drug molecules within the particle matrix. 13,14 Furthermore, these can accommodate both hydrophilic and hydrophobic substances, and nanoparticles allow for versatile routes of administration, encompassing oral intake and inhalation. 15−17 Researchers have proposed a wide range of applications of drug-loaded nanoparticles designed to precisely target tumor sites. ...
... 6 One of the most relevant challenges in nanomedicine is obtaining nanocarriers with simple and sustainable synthetic routes, high drug loading capacity, robustness in physiological environments, and good biocompatibility. 7,8 In this context, nanomaterials based on polyelectrolytes are especially interesting due to the great diversity and availability of this class of polymer. 9,10 In addition, many of these macromolecules are easily solubilized in aqueous media, which allow highly sustainable preparation routes to be applied without the need for the use of toxic and expensive organic solvents. ...
Biobased materials are goods whose primary ingredients were first taken from living things. The hybrid science known as nanobiotechnology, which was created by the fusion of the two potent technologies of nanotechnology and biotechnology, is a reflection of science’s expanding capacity to conduct research at scales higher than the molecular one and produce useful outcomes. The significance of all of them is shown in the large number of research articles on nanocomposites and bionanomaterials. Their naturally formed, biocompatible, biodegradable aqueous polymeric and benign substrates make them ideal for a wide range of biomedical applications. Certain tissues and living organisms are considered to be a representative example of a nanocomposite, which is the reason nanostructured materials are believed to play a significant role in biomedical research. Tissue engineering and implants as well as nanomedicine are two areas where nanobiotechnology is useful. Research and development in several fields of nanobiotechnology aims to provide extremely effective biosensors, nanoscale microchips, molecular switches, and tissue analogs for the skin, muscles, bones, and other human organs. Many biomedical applications, including innovative tissue engineering scaffolds, focused drug delivery systems, biosensors, etc., have been researched for metallic, ceramic, polymeric, and composite nanomaterials in-depth. Tissue engineering and health care cover the identification, management, and avoidance of diseases with a long-term objective of improving people’s quality of life by developing modern facilities materials and therapies based on scaffolds and drug delivery. The main objective of this review is to give the readers an overview of the application of bio-based nanomaterial.
Biocatalysis is increasingly being explored for the sustainable development of green industry. Though enzymes show great industrial potential with their high efficiency, specificity, and selectivity, they suffer from poor usability and stability under abiological conditions. To solve these problems, researchers have fabricated nano‐ and micro‐sized biocatalytic reactors based on the self‐assembly of various polymers, leading to highly stable, functional, and reusable biocatalytic systems. This Review highlights recent progress in self‐assembled polymeric nano‐ and microreactors for biocatalytic synthesis, including polymersomes, reverse micelles, polymer emulsions, Pickering emulsions, and static emulsions. We categorize these reactors into monophasic and biphasic systems and discuss their structural characteristics and latest successes with representative examples. We also consider the challenges and potential solutions associated with the future development of this field.
The first two mRNA vaccines against infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that were approved by regulators require a cold chain and were designed to elicit systemic immunity via intramuscular injection. Here we report the design and preclinical testing of an inhalable virus-like-particle as a COVID-19 vaccine that, after lyophilisation, is stable at room temperature for over three months. The vaccine consists of a recombinant SARS-CoV-2 receptor-binding domain (RBD) conjugated to lung-derived exosomes which, with respect to liposomes, enhance the retention of the RBD in both the mucus-lined respiratory airway and in lung parenchyma. In mice, the vaccine elicited RBD-specific IgG antibodies, mucosal IgA responses and CD4+ and CD8+ T cells with a Th1-like cytokine expression profile in the animals’ lungs, and cleared them of SARS-CoV-2 pseudovirus after a challenge. In hamsters, two doses of the vaccine attenuated severe pneumonia and reduced inflammatory infiltrates after a challenge with live SARS-CoV-2. Inhalable and room-temperature-stable virus-like particles may become promising vaccine candidates. An inhalable virus-like-particle consisting of exosomes decorated with a recombinant SARS-CoV-2 receptor-binding domain is stable at room temperature and elicits systemic and mucosal immune responses in small animals.
Vaults are ubiquitous ribonucleoprotein particles involved in a diversity of cellular processes, with promising applications as nanodevices for delivery of multiple cargos. The vault shell is assembled by the symmetrical association of multiple copies of the major vault protein that, initially, generates half vaults. The pairwise, anti-parallel association of two half vaults produces whole vaults. Here, using a combination of vault recombinant reconstitution and structural techniques, we characterized the molecular determinants for the vault opening process. This process commences with a relaxation of the vault waist, causing the expansion of the inner cavity. Then, local disengagement of amino-terminal domains at the vault midsection seeds a conformational change that leads to the aperture, facilitating access to the inner cavity where cargo is hosted. These results inform a hitherto uncharacterized step of the vault cycle and will aid current engineering efforts leveraging vault for tailored cargo delivery.
Liposomes are well-recognized and essential nano-sized drug delivery systems. Liposomes are phospholipid vesicles comprised of cell membrane components and have been employed as artificial cell models to mimic structure and functions of cells and are of immense use in various biological analyses. Liposomes acquire great advantages and provide wide range of applications as useful drug carriers in pre-clinical and clinical trials. This review summarizes exclusively on scalable techniques for liposome preparation and focuses on the strengths and limitations with respect to industrial applicability. Also, this review discusses the updated recent advancements in biomedical applications with a mention of key highlights of commercially available formulations, clinical trials and patents in recent past. Furthermore, this review also provides brief information of the classification, composition and characterization of liposomes.
Considerable progress has been made in synthesizing “intelligent”, biodegradable hydrogels that undergo rapid changes in physicochemical properties once exposed to external stimuli. These advantageous properties of stimulus‐triggered materials make them highly appealing to diverse biomedical applications. Of late, research on the incorporation of light‐triggered nanoparticles (NPs) into polymeric hydrogel networks has gained momentum due to their ability to remotely tune hydrogel properties using facile, contact‐free approaches, such as adjustment of wavelength and intensity of light source. These multi‐functional NPs, in combination with tissue‐mimicking hydrogels, are increasingly being used for on‐demand drug release, preparing diagnostic kits, and fabricating smart scaffolds. Here, the authors discuss the atomic behavior of different NPs in the presence of light, and critically review the mechanisms by which NPs convert light stimuli into heat energy. Then, they explain how these NPs impact the mechanical properties and rheological behavior of NPs‐impregnated hydrogels. Understanding the rheological behavior of nanocomposite hydrogels using different sophisticated strategies, including computer‐assisted machine learning, is critical for designing the next generation of drug delivery systems. Next, they highlight the salient strategies that have been used to apply light‐induced nanocomposites for diverse biomedical applications and provide an outlook for the further improvement of these NPs‐driven light‐responsive hydrogels.
Methods to deliver gene editing agents in vivo as ribonucleoproteins could offer safety advantages over nucleic acid delivery approaches. We report the development and application of engineered DNA-free virus-like particles (eVLPs) that efficiently package and deliver base editor or Cas9 ribonucleoproteins. By engineering VLPs to overcome cargo packaging, release, and localization bottlenecks, we developed fourth-generation eVLPs that mediate efficient base editing in several primary mouse and human cell types. Using different glycoproteins in eVLPs alters their cellular tropism. Single injections of eVLPs into mice support therapeutic levels of base editing in multiple tissues, reducing serum Pcsk9 levels 78% following 63% liver editing, and partially restoring visual function in a mouse model of genetic blindness. In vitro and in vivo off-target editing from eVLPs was virtually undetected, an improvement over AAV or plasmid delivery. These results establish eVLPs as promising vehicles for therapeutic macromolecule delivery that combine key advantages of both viral and nonviral delivery.
Chronic kidney disease (CKD) is defined as structural and functional abnormalities of the kidney due to inflammation and fibrosis. We investigated the therapeutic effects of exosomes secreted by melatonin-stimulated mesenchymal stem cells (Exocue) on the functional recovery of the kidney in a CKD mouse model. Exocue upregulated gene expression of micro RNAs (miRNAs) associated with anti-inflammatory and anti-fibrotic effects. Exocue-treated groups exhibited low tumor necrosis factor-α and transforming growth factor-β levels in serum and fibrosis inhibition in kidney tissues mediated through regulation of cell apoptosis and proliferation of fibrosis-related cells. Exocue treatment decreased the gene expression of CKD progression-related miRNAs. Moreover, the CKD severity was alleviated in the Exocue group via upregulation of aquaporin 2 and 5 levels and reduction of blood urea nitrogen and creatinine, resulting in functional recovery of the kidney. In conclusion, Exocue could be a novel therapeutic agent for treating CKD by regulating inflammation and fibrosis.
Functional delivery of mRNA has high clinical potential. Previous studies established that mRNAs can be delivered to cells in vitro and in vivo via RNA-loaded lipid nanoparticles (LNPs). Here we describe an alternative approach using exosomes, the only biologically normal nanovesicle. In contrast to LNPs, which elicited pronounced cellular toxicity, exosomes had no adverse effects in vitro or in vivo at any dose tested. Moreover, mRNA-loaded exosomes were characterized by efficient mRNA encapsulation (∼90%), high mRNA content, consistent size, and a polydispersity index under 0.2. Using an mRNA encoding the red light-emitting luciferase Antares2, we observed that mRNA-loaded exosomes were superior to mRNA-loaded LNPs at delivering functional mRNA into human cells in vitro. Injection of Antares2 mRNA-loaded exosomes also led to strong light emission following injection into the vitreous fluid of the eye or into the tissue of skeletal muscle in mice. Furthermore, we show that repeated injection of Antares2 mRNA-loaded exosomes drove sustained luciferase expression across six injections spanning at least 10 weeks, without evidence of signal attenuation or adverse injection site responses. Consistent with these findings, we observed that exosomes loaded with mRNAs encoding immunogenic forms of the SARS-CoV-2 Spike and Nucleocapsid proteins induced long-lasting cellular and humoral responses to both. Taken together, these results demonstrate that exosomes can be used to deliver functional mRNA to and into cells in vivo.
In the last decade, the advent of 3D printing for tissue engineering and regenerative medicine has engendered great interest for those involved in skin repair and regeneration. 3D bioprinting allows spatial distribution of skin cells into predefined custom-made structures to produce living skin mimics on the bench for grafting or drug testing. The key aspect of 3D bioprinting lies in the formulation of printable bioinks serving as matrix mimics to house skin cells, alongside an appropriate combination of cells. In this review, bioink formulations, cell combinations, as well as manufacturing methods exploited to develop 3D bioprinted constructs for skin regeneration are summarized. Issues to do with the selection of suitable materials and cells to ensure the functionality of the resulting skin constructs and fabrication of skin appendages are also addressed.
The main purpose herein is to provide an up‐to‐date review on noninvasive biomimetic, bioinspired, and bioengineered drug delivery system (DDS). Noninvasive DDS is an ever‐growing field critical for the applicability of drugs. It offers noninvasive administration routes with improved controlled, targeted, and triggered drug delivery. Noninvasive DDS employ many approaches and strategies, such as, nano‐ and microparticles, lipid‐based systems, sonophoresis, electrophoresis and iontophoresis, penetration enhancers, microneedles, and gels. The last decade seen a surge in research papers employing the paradigms of biomimicry, bioinspiration, and bioengineering. However, since the use of these terms in noninvasive DDS field is often inconsistent and unclear, some generalized perspectives are provided on the possible usage of these terms in future publications. Additionally, a critical discussion on the novelty and origins of these paradigms is provided. The advantages and disadvantages of each of the noninvasive routes and their current main limitations are summarized. The main aspects of indicated fields are discussed: The unique physiology of the related tissues, the main hurdles for mass transport, the various DDS tested, and materials selection. Finally, the basic concepts and therapeutic effects of these DDS are discussed and future venues for noninvasive biomimetic, bioinspired, and bioengineered DDS research are proposed. Various strategies used in noninvasive biomimetic, bioinspired, and bioengineered drug delivery system (DDS) are described. Details are provided on the unique physiology of related tissues, main hurdles for mass transport, and materials selection. A discussion on the novelty and origins of these paradigms is provided, and the future venues for biomimetic, bioinspired, and bioengineered noninvasive DDS research are proposed.
Hydrogels can be fabricated and designed to exert direct control over stem cells' adhesion and differentiation. In this study, we have investigated the use of polydopamine (pDA)-treatment as a binding platform for bioactive compounds to create a versatile gelatin-alginate (Gel-Alg) hydrogel for tissue engineering applications. Precisely, pDA was used to modify the surface properties of the hydrogel and better control the adhesion and osteogenic differentiation of human adipose-derived stem cells (hASCs). pDA enabled the adsorption of different types of bioactive molecules, including a model osteoinductive drug (dexamethasone) as well as a model pro-angiogenic peptide (QK). The pDA treatment efficiently retained the drug and the peptide compared to the untreated hydrogel and proved to be effective in controlling the morphology, cell area, and osteogenic differentiation of hASCs. Overall, the findings of this study confirm the efficacy of pDA treatment as a valuable strategy to modulate the biological properties of biocompatible Gel-Alg hydrogels and further extend their value in regenerative medicine.
Exosomes derived from mesenchymal stem cells (MSC-Exo) are effective in modulating immunity. However, the role of MSC-Exo in clear cell renal cell carcinoma (ccRCC) is unclear. Our study was performed to identify if exosomal microRNA (miRNA) can be used as potential noninvasive biomarkers for ccRCC therapy. An orthotopic ccRCC mouse model was established, followed by MSC-Exo injection (1 mL, 20 μg/mL). The metastases of tumors were observed using HE staining, while number of dendritic cells, natural killing (NK) T cells and CD8+ T cells was measured using flow cytometry. It was observed that MSC-Exo treatment significantly inhibited metastasis and growth of tumors, and improved immune response in vivo. As for in vitro assay, naive T cells were treated with MSC-Exo, followed by detection of T cell proliferation using EdU staining and CFSE assay. Results also showed that MSC-Exo facilitated sensitivity of ccRCC cells to NK T cells. Our experimental data further showed that miR-182 could be delivered by MSC-Exo in ccRCC, which targeted vascular endothelial growth factor A (VEGFA), as dual-luciferase reporter assays validated. In conclusion, miR-182 contained in MSC-Exo promoted immune response of T cells by suppressing VEGFA expression, thus alleviating ccRCC development.
Management of non-healing and slow to heal diabetic wounds is a major concern in healthcare across the world. Numerous techniques have been investigated to solve the issue of delayed wound healing, though, mostly unable to promote complete healing of diabetic wounds due to the lack of proper cell proliferation, poor cell-cell communication, and higher chances of wound infections. These challenges can be minimized by using hydrogel based wound healing patches loaded with bioactive agents. Gelatin methacrylate (GelMA) has been proven to be a highly cell friendly, cell adhesive, and inexpensive biopolymer for various tissue engineering and wound healing applications. In this study, S-Nitroso-N-acetylpenicillamine (SNAP), a nitric oxide (NO) donor, was incorporated in a highly porous GelMA hydrogel patch to improve cell proliferation, facilitate rapid cell migration, and enhance diabetic wound healing. We adopted a visible light crosslinking method to fabricate this highly porous biodegradable but relatively stable patch. Developed patches were characterized for morphology, NO release, cell proliferation and migration, and diabetic wound healing in a rat model. The obtained results indicate that SNAP loaded visible light crosslinked GelMA hydrogel patches can be highly effective in promoting diabetic wound healing.
Ischemic stroke remains a major cause of death, and anti-inflammatory strategies hold great promise for preventing major brain injury during reperfusion. In the past decade, stem cell-derived extracellular vesicles (EVs) have emerged as novel therapeutic effectors in immune modulation. However, the intravenous delivery of EVs into the ischemic brain remains a challenge due to poor targeting of unmodified EVs, and the costs of large-scale production of stem cell-derived EVs hinder their clinical application.
Methods: EVs were isolated from a human neural progenitor cell line, and their anti-inflammatory effects were verified in vitro. To attach targeting ligands onto EVs, we generated a recombinant fusion protein containing the arginine-glycine-aspartic acid (RGD)-4C peptide (ACDCRGDCFC) fused to the phosphatidylserine (PS)-binding domains of lactadherin (C1C2), which readily self-associates onto the EV membrane. Subsequently, in a middle cerebral artery occlusion (MCAO) mouse model, the RGD-C1C2-bound EVs (RGD-EV) were intravenously injected through the tail vein, followed by fluorescence imaging and assessment of proinflammatory cytokines expression and microglia activation.
Results: The neural progenitor cell-derived EVs showed intrinsic anti-inflammatory activity. The RGD-EV targeted the lesion region of the ischemic brain after intravenous administration, and resulted in a strong suppression of the inflammatory response. Furthermore, RNA sequencing revealed a set of 7 miRNAs packaged in the EVs inhibited MAPK, an inflammation related pathway.
Conclusion: These results point to a rapid and easy strategy to produce targeting EVs and suggest a potential therapeutic agent for ischemic stroke.
Exosomes (Exos) are nanosized vesicles (around 100 nm) that recently serve as a promising drug carrier with high biocompatibility and low immunogenicity. Previous studies showed that Exos secreted from mesenchymal stem cells (MSCs) provide protection for concanavalin A (Con A)-induced liver injury. In this study, the protective effect of Exos is confirmed, and dexamethasone (DEX)-incorporated Exos named Exo@DEX are prepared. It is then investigated whether Exo@DEX can function more efficiently compared to free drugs and naive Exos in a Con A-induced autoimmune hepatitis (AIH) mouse model. The results show that Exo@DEX efficiently improves the accumulation of DEX in AIH in the liver. These data suggest that Exo@DEX is a promising drug carrier for AIH and could have applications in other diseases.
Virus-like particles (VLPs) are virus-derived structures made up of one or more different molecules with the ability to self-assemble, mimicking the form and size of a virus particle but lacking the genetic material so they are not capable of infecting the host cell. Expression and self-assembly of the viral structural proteins can take place in various living or cell-free expression systems after which the viral structures can be assembled and reconstructed. VLPs are gaining in popularity in the field of preventive medicine and to date, a wide range of VLP-based candidate vaccines have been developed for immunization against various infectious agents, the latest of which is the vaccine against SARS-CoV-2, the efficacy of which is being evaluated. VLPs are highly immunogenic and are able to elicit both the antibody- and cell-mediated immune responses by pathways different from those elicited by conventional inactivated viral vaccines. However, there are still many challenges to this surface display system that need to be addressed in the future. VLPs that are classified as subunit vaccines are subdivided into enveloped and non- enveloped subtypes both of which are discussed in this review article. VLPs have also recently received attention for their successful applications in targeted drug delivery and for use in gene therapy. The development of more effective and targeted forms of VLP by modification of the surface of the particles in such a way that they can be introduced into specific cells or tissues or increase their half-life in the host is likely to expand their use in the future. Recent advances in the production and fabrication of VLPs including the exploration of different types of expression systems for their development, as well as their applications as vaccines in the prevention of infectious diseases and cancers resulting from their interaction with, and mechanism of activation of, the humoral and cellular immune systems are discussed in this review.
The development of a safe and effective SARS-CoV-2 vaccine is a public health priority. We designed subunit vaccine candidates using self-assembling ferritin nanoparticles displaying one of two multimerized SARS-CoV-2 spikes: full-length ectodomain (S-Fer) or a C-terminal 70 amino-acid deletion (SΔC-Fer). Ferritin is an attractive nanoparticle platform for production of vaccines, and ferritin-based vaccines have been investigated in humans in two separate clinical trials. We confirmed proper folding and antigenicity of spike on the surface of ferritin by cryo-EM and binding to conformation-specific monoclonal antibodies. After a single immunization of mice with either of the two spike ferritin particles, a lentiviral SARS-CoV-2 pseudovirus assay revealed mean neutralizing antibody titers at least 2-fold greater than those in convalescent plasma from COVID-19 patients. Additionally, a single dose of SΔC-Fer elicited significantly higher neutralizing responses as compared to immunization with the spike receptor binding domain (RBD) monomer or spike ectodomain trimer alone. After a second dose, mice immunized with SΔC-Fer exhibited higher neutralizing titers than all other groups. Taken together, these results demonstrate that multivalent presentation of SARS-CoV-2 spike on ferritin can notably enhance elicitation of neutralizing antibodies, thus constituting a viable strategy for single-dose vaccination against COVID-19.
The stimulator of interferon genes (STING) pathway plays an important role in the immune surveillance of cancer and, accordingly, agonists of STING signaling have recently emerged as promising therapeutics for remodeling of the immunosuppressive tumor microenvironment (TME) and enhancing response rates to immune checkpoint inhibitors. 2′3′-cyclic guanosine monophosphate–adenosine monophosphate (2′3′-cGAMP) is the endogenous ligand for STING, but is rapidly metabolized and poorly membrane permeable, restricting its use to intratumoral administration. Nanoencapsulation has been shown to allow for systemic administration of cGAMP and other cyclic dinucleotides (CDN), but little is known about how nanocarriers affect important pharmacological properties that impact the efficacy and safety of CDNs. Using STING-activating nanoparticles (STING-NPs) – a polymersome platform designed to enhance cGAMP delivery – we investigate the pharmacokinetic (PK)-pharmacodynamic (PD) relationships that underlie the ability of intravenously (i.v.) administered STING-NPs to induce STING activation and inhibit tumor growth. First, we demonstrate that nanoencapsulation improves the half-life of encapsulated cGAMP by 40-fold, allowing for sufficient accumulation of cGAMP in tumors and activation of the STING pathway in the TME as assessed by western blot analysis and gene expression profiling. Nanoparticle delivery also changes the biodistribution profile, resulting in increased cGAMP accumulation and STING activation in the liver and spleen, which we identify as dose limiting organs. As a consequence of STING activation in tumors, i.v. administered STING-NPs reprogram the TME towards a more immunogenic antitumor milieu, characterized by an influx of >20-fold more CD4⁺ and CD8⁺ T-cells. Consequently, STING-NPs increased response rates to αPD-L1 antibodies, resulting in significant improvements in median survival time in a B16-F10 melanoma model. Additionally, we confirmed STING-NP monotherapy in an additional melanoma (YUMM1.7) and breast adenocarcinoma (E0771) models leading to >50% and 80% reduction in tumor burden, respectively, and significant increases in median survival time. Collectively, this work provides an examination of the PK-PD relationship governing STING activation upon systemic delivery using STING-NPs, providing insight for future optimization for nanoparticle-based STING agonists and other immunomodulating nanomedicines.
Natural, extracellular membrane vesicles secreted by Gram-negative bacteria, outer membrane vesicles (OMVs), contain numerous pathogen-associated molecular patterns which can activate systemic immune responses. Previous studies have shown that OMVs induce strong IFN-γ- and T cell-mediated anti-tumor effects in mice. However, IFN-γ is known to upregulate immunosuppressive factors in the tumor microenvironment, especially the immune checkpoint programmed death 1 ligand 1 (PD-L1), which may hamper T cell function and limit immunotherapeutic effectiveness. Here, we report the development of genetically engineered OMVs whose surface has been modified by insertion of the ectodomain of programmed death 1 (PD1). This genetic modification does not affect the ability of OMVs to trigger immune activation. More importantly, the engineered OMV-PD1 can bind to PD-L1 on the tumor cell surface and facilitate its internalization and reduction, thereby protecting T cells from the PD1/PD-L1 immune inhibitory axis. Through the combined effects of immune activation and checkpoint suppression, the engineered OMVs drive the accumulation of effector T cells in the tumor, which, in turn, leads to a greater impairment of tumor growth, compared with not only native OMVs but also the commonly used PD-L1 antibody. In conclusion, this work demonstrates the potential of bioengineered OMVs as effective immunotherapeutic agents that can comprehensively regulate the tumor immune microenvironment to effect markedly increased anti-tumor efficacy.
Due to a strong retardation effect of o-nitrobenzyl ester on polymerization, it is still a great challenge to prepare amphiphilic block copolymers for polymersomes with a o-nitrobenzyl ester-based hydrophobic block. Herein, we present one such solution to prepare amphiphilic block copolymers with pure poly (o-nitrobenzyl acrylate) (PNBA) as the hydrophobic block and poly (N,N’-dimethylacrylamide) (PDMA) as the hydrophilic block using bulk reversible addition-fragmentation chain transfer (RAFT) polymerization of o-nitrobenzyl acrylate using a PDMA macro-RAFT agent. The developed amphiphilic block copolymers have a suitable hydrophobic/hydrophilic ratio and can self-assemble into photoresponsive polymersomes for co-loading hydrophobic and hydrophilic cargos into hydrophobic membranes and aqueous compartments of the polymersomes. The polymersomes demonstrate a clear photo-responsive characteristic. Exposure to light irradiation at 365 nm can trigger a photocleavage reaction of o-nitrobenzyl groups, which results in dissociation of the polymersomes with simultaneous co-release of hydrophilic and hydrophobic cargoes on demand. Therefore, these polymersomes have great potential as a smart drug delivery nanocarrier for controllable loading and releasing of hydrophilic and hydrophobic drug molecules. Moreover, taking advantage of the conditional releasing of hydrophilic and hydrophobic drugs, the drug delivery system has potential use in medical applications such as cancer therapy.
Exosomes are a subset of extracellular vesicles that carry specific combinations of proteins, nucleic acids, metabolites, and lipids. Mounting evidence suggests that exosomes participate in intercellular communication and act as important molecular vehicles in the regulation of numerous physiological and pathological processes, including cancer development. Exosomes are released by various cell types under both normal and pathological conditions, and they can be found in multiple bodily fluids. Moreover, exosomes carrying a wide variety of important macromolecules provide a window into altered cellular or tissue states. Their presence in biological fluids renders them an attractive, minimally invasive approach for liquid biopsies with potential biomarkers for cancer diagnosis, prediction, and surveillance. Due to their biocompatibility and low immunogenicity and cytotoxicity, exosomes have potential clinical applications in the development of innovative therapeutic approaches. Here, we summarize recent advances in various technologies for exosome isolation for cancer research. We outline the functions of exosomes in regulating tumor metastasis, drug resistance, and immune modulation in the context of cancer development. Finally, we discuss prospects and challenges for the clinical development of exosome-based liquid biopsies and therapeutics.
Atherosclerosis (AS), the underlying cause of most cardiovascular events, is one of the most common causes of human morbidity and mortality worldwide due to the lack of an efficient strategy for targeted therapy. In this work, we aimed to develop an ideal biomimetic nanoparticle for targeted AS therapy.
Methods: Based on macrophage “homing” into atherosclerotic lesions and cell membrane coating nanotechnology, biomimetic nanoparticles (MM/RAPNPs) were fabricated with a macrophage membrane (MM) coating on the surface of rapamycin-loaded poly (lactic-co-glycolic acid) copolymer (PLGA) nanoparticles (RAPNPs). Subsequently, the physical properties of the MM/RAPNPs were characterized. The biocompatibility and biological functions of MM/RAPNPs were determined in vitro. Finally, in AS mouse models, the targeting characteristics, therapeutic efficacy and safety of the MM/RAPNPs were examined.
Results: The advanced MM/RAPNPs demonstrated good biocompatibility. Due to the MM coating, the nanoparticles effectively inhibited the phagocytosis by macrophages and targeted activated endothelial cells in vitro. In addition, MM-coated nanoparticles effectively targeted and accumulated in atherosclerotic lesions in vivo. After a 4-week treatment program, MM/RAPNPs were shown to significantly delay the progression of AS. Furthermore, MM/RAPNPs displayed favorable safety performance after long-term administration.
Conclusion: These results demonstrate that MM/RAPNPs could efficiently and safely inhibit the progression of AS. These biomimetic nanoparticles may be potential drug delivery systems for safe and effective anti-AS applications.
Mesoporous silica nanoparticles (MSNs) functionalized with redox‐sensitive or pH‐sensitive nanovalves for doxorubicin delivery and release by using recombinant human H chain ferritin (HFn) as a cap have been designed and fabricated. In both cases, transmission electron microscope observatory, dynamic light scattering change, Fourier transform infrared spectra examination, thermogravimetric analysis show that HFn can be chemically bonded to MSNs while retaining its ability to target transferrin receptor 1 (TfR1). Cargo loading and release studies demonstrate that HFn is an efficient capping agent, blocking the pores of MSN preventing cargo molecules from diffusing out, and is responsive to redox stimuli or pH changes. More importantly, HFn can not only cap the MSNs, but also enables targeted cargo delivery to malignant cells by binding to the TfR1 that has been overexpressed in various tumors, which can be reflected by the cell viability and fluorescence microscope analysis results comparing with cyclodextrin as the capping agent and TfR1 blocking assay. The in vivo study reveals the excellent efficacy of doxorubicin loaded and HFn capped MSNs on suppression of tumor growth. The new developed drug delivery system features mutually benefit and mutually support, providing strategy for achieving specific‐site therapeutics delivery systems.
In the present paper, Mohosen et al. [1] reviewed the evidence of the interaction between virus-like particles (VLPs) and the innate immune system. [...]
Non-communicable diseases (NCDs) are the world’s leading causes of death and disability, with cardiovascular disease (CVD) accounting for half of NCD deaths. An ambitious global target established by the United Nations Sustainable Development Goals – indicator 3.4.1 – aims to reduce the risk of premature death among people aged 30–69 years from CVD, cancer, diabetes, and chronic lung disease by one third by 2030. This article reviews the science and practice informing what is required to achieve this target, identifying seven interventions that can accelerate progress: 1) tobacco control; 2) treatment to reduce cardiovascular risk; 3) reduction of dietary sodium; 4) reduction of household air pollution; 5) elimination of artificial trans fat; 6) reduction of alcohol use; and 7) prevention, detection, and treatment of cancers. Achieving the target is possible – there has already been progress in some areas, particularly related to CVD reduction – but only if there is faster, more concerted action.
Metastatic peritoneal carcinoma (mPC) is a deadly disease without effective treatment. To improve treatment of this disease, a recently developed hyperthermic intraperitoneal chemotherapy (HIPEC) has emerged as the standard of care. However, the efficacy of this approach is limited by inefficient drug penetration and rapidly developed drug resistance. Herein, a nanotechnology approach is reported that is designed to improve drug delivery to mPC and to augment the efficacy of HIPEC through delivery of chemoimmunotherapy. First, the drug delivery efficiency of HIPEC is determined and it is found that chemotherapy agents cannot be efficiently delivered to large tumors nodules. To overcome the delivery hurdle, genetically engineered exosomes‐thermosensitive liposomes hybrid NPs, or gETL NPs, are then synthesized, and it is demonstrated that the NPs after intravenous administration efficiently penetrates into mPC tumors and releases payloads at the hypothermia condition of HIPEC. Last, it is shown that, when granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) and docetaxel are co‐delivered, gETL NPs effectively inhibit tumor development and the efficacy is enhanced when HIPEC is co‐administered. The study provides a strategy to improve drug delivery to mPCs and offers a promising approach to improve treatment of the disease through combination of locoregional delivery of HIPEC and systemic delivery of chemoimmunotherapy via gETL NPs.
Background:
The well-known fact that avian pathogenic Escherichia coli (APEC) is harder to prevent due to its numerous serogroups has promoted the development of biological immunostimulatory materials as new vaccine candidates in poultry farms. Bacterial outer membrane vesicles (OMVs), known as spherical nanovesicles enriched with various immunostimulants, are naturally secreted by Gram-negative bacteria, and have gained much attention for developing effective vaccine candidates. Recent report has demonstrated that OMVs of APEC O78 can induce protective immunity in chickens. Here, a novel multi-serogroup OMVs (MOMVs) vaccine was developed to achieve cross-protection against APEC infection in broiler chickens.
Results:
In this study, OMVs produced by three APEC strains were isolated, purified and prepared into MOMVs by mixing these three OMVs. By using SDS-PAGE and LC-MS/MS, 159 proteins were identified in MOMVs and the subcellular location and biological functions of 20 most abundant proteins were analyzed. The immunogenicity of MOMVs was evaluated, and the results showed that MOMVs could elicit innate immune responses, including internalization by chicken macrophage and production of immunomodulatory cytokines. Vaccination with MOMVs induced specific broad-spectrum antibodies as well as Th1 and Th17 immune responses. The animal experiment has confirmed that immunization with an appropriate dose of MOMVs could not cause any adverse effect and was able to reduce bacteria loads and pro-inflammatory cytokines production, thus providing effective cross-protection against lethal infections induced by multi-serogroup APEC strains in chickens. Further experiments indicated that, although vesicular proteins were able to induce stronger protective efficiency than lipopolysaccharide, both vesicular proteins and lipopolysaccharide are crucial in MOMVs-mediated protection.
Conclusions:
The multi-serogroup nanovesicles produced by APEC strains will open up a new way for the development of next generation vaccines with low toxicity and broad protection in the treatment and control of APEC infection.
PurposeGlioblastoma prognosis remains grim despite maximal, multimodal management. Recent literature has demonstrated an increase in research devoted to experimental treatments, particularly those relying on the foundations of active immunotherapy with promising results. We hypothesize that the utilization of bioengineered recombinant vault nanoparticles coupled with glioma-associated antigens, such as the NY-ESO-1 peptide, may be capable of stimulating native dendritic cell (DC) maturation and inducing an anti-tumor response.Methods
Immature DCs were cultured from the bone marrow of 4–6-week-old C57BL/6 mice. The three treatment groups consisted of: (1) DC and media, (2) DC with mCherry vault, and (3) DC with NYESO and vault. DC maturity was assessed via flow cytometric evaluation of CD11c, CD86, and MHC-II. Increase in CD86 Median Fluorescence Intensity (MFI) was analyzed in the CD11c+CD86+MHC-II+ population to determine the extent of maturationResultsOur findings suggest that CP-MVP-NY-ESO-1-INT recombinant vault nanoparticles are efficiently bioengineered with exceptional integrity, are quickly internalized by immature DCs for antigen processing, and result in DC maturation.Conclusion
This study reports our preliminary results, which demonstrate the feasibility and progress regarding our immunotherapeutic technique utilizing NY-ESO-1 packaged vault nanoparticles to prime DCs for subsequent anti-cancer therapies.
A limitation of using exosomes to their fullest potential is their limited secretion from cells, a major bottleneck to efficient exosome production and application. This is especially true for mesenchymal stem cells (MSCs), which can self-renew but have a limited expansion capacity, undergoing senescence after only a few passages, with exosomes derived from senescent stem cells showing impaired regenerative capacity compared to young cells. Here, we examined the effects of small molecule modulators capable of enhancing exosome secretion from MSCs. The treatment of MSCs with a combination of N-methyldopamine and norepinephrine robustly increased exosome production by three-fold without altering the ability of the MSC exosomes to induce angiogenesis, polarize macrophages to an anti-inflammatory phenotype, or downregulate collagen expression. These small molecule modulators provide a promising means to increase exosome production by MSCs.
Extracellular vesicles are produced by species across all domains of life, suggesting that vesiculation represents a fundamental principle of living matter. In Gram-negative bacteria, membrane vesicles (MVs) can originate either from blebs of the outer membrane or from endolysin-triggered explosive cell lysis, which is often induced by genotoxic stress. Although less is known about the mechanisms of vesiculation in Gram-positive and Gram-neutral bacteria, recent research has shown that both lysis and blebbing mechanisms also exist in these organisms. Evidence has accumulated over the past years that different biogenesis routes lead to distinct types of MV with varied structure and composition. In this Review, we discuss the different types of MV and their potential cargo packaging mechanisms. We summarize current knowledge regarding how MV composition determines their various functions including support of bacterial growth via the disposal of waste material, nutrient scavenging, export of bioactive molecules, DNA transfer, neutralization of phages, antibiotics and bactericidal functions, delivery of virulence factors and toxins to host cells and inflammatory and immunomodulatory effects. We also discuss the advantages of MV-mediated secretion compared with classic bacterial secretion systems and we introduce the concept of quantal secretion.
The most recent WHO statistics of the year 2020 shows that lung cancer accounts for the maximum cancer mortality cases, with 1.8 million deaths annually. The current treatment strategies for lung cancer involve the three classical approaches adopted in all types of cancer, that is, chemotherapy, radiation therapy, and surgical procedures. Apart from these, radiofrequency ablation, immunotherapy, and palliative care is provided to improve the prognosis of the patients. However, the ever-increasing number of about 2.2 million new cases of lung cancer each year along with an increase in its causative factors like tobacco smoking and air pollutants, demand newer and more effective therapies to control the disease. The treatment is usually started with chemotherapy, which is mostly given parenterally, which gives higher systemic concentration than the lung tissue, leading to non-selective action and generally has lower patient compliance. In this article, we aim to review the use of nanocarriers like carbon nanotubes, dendrimers, quantum dots, micelles, magnetic nanoparticles, gold nanoparticles, and liposomes for targeted lung cancer treatment. Comparison of several clinical trials shows the superiority of lipid-based nanocarriers called liposomes, and their use through the pulmonary route to control the cancer growth as well as selective accumulation in the lung tissue, slow-release, and higher effectiveness, with least adverse effects. Liposomes are a tiny bubble, spherical vesicles which have at least one lipid bilayer. We have also addressed the challenges related to factors like drug resistance, particle size, etc., faced during incorporation of antineoplastic agents into the liposomes and ways to overcome them. Lastly, we have addressed the wide scope of inhalational liposomal treatment as a course of medical care in lung cancer and its future prospects.
Vaccination has become an increasingly attractive strategy for protecting against antibiotic-resistant infections. Nanovaccines based on the outer membrane from Gram-negative bacteria are appealing due to their multiantigenic nature and inherent immunogenicity. Here, we develop cellular nanodiscs made of bacterial outer membrane (OM-NDs), as a platform for antibacterial vaccination. Using Pseudomonas aeruginosa as a model pathogen, the resulting OM-NDs can effectively interact with antigen-presenting cells, exhibiting accelerated uptake and an improved capacity for immune stimulation. With their small size, the OM-NDs are also capable of efficiently transporting to the lymph nodes after in vivo administration. As a result, the nanovaccine is effective at eliciting potent humoral and cellular immune responses against P. aeruginosa. In a murine model of pneumonia, immunization with OM-NDs confers strong protection against subsequent lung infection, resulting in improved survival, reduced bacterial loads, and alleviation of immune overactivation. Overall, this report illustrates the advantages of cellular nanodiscs, which can be readily generalized to other pathogens and may be applied toward other biomedical applications.
Natural polymer-based hydrogels are excellent for encapsulating hydrophilic drugs, but they are mechanically weak and degrade easily. In this communication, we exploit the electrostatic interaction between nanosilicates (nSi) and gelatin methacrylate (GelMA) to form a mechanically tough nanocomposite hydrogel for pharmaceutical drug delivery. These hydrogels, prepared at subzero temperatures to form cryogels, displayed macroporous structures, which favors cell infiltration. The designed tough cryogel also showed a slower rate of degradation. Furthermore, we encapsulated the small molecule metformin and sustained the drug release under physiological conditions. Cryogel-loaded metformin reduced the effect of endothelial cell injury caused by nutrient deprivation in vitro. Finally, we hypothesize that this versatile nanocomposite material will find use in diverse biomedical applications.
Extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) have been evaluated in many studies as promising therapeutic agents for pulmonary hypertension (PH). However, low yields and heterogeneity are a major barrier in the translational utility of EVs for clinical studies. To address these limitations, we fabricated MSCs derived nanovesicles (MSC-NVs) by serial extrusion through filters resulting in MSC-NVs with characteristics similar to conventional EVs but with much higher production yields. Herein, we examined the therapeutic efficacy of MSC-NVs in preclinical models of PH in vitro and in vivo. Intervention with MSC-NVs improved the core pathologies of monocrotaline (MCT) induced PH in rat. Intravenous administration of MSC-NVs resulted in significant uptake within hypertensive lungs, pulmonary artery lesions and especially in pulmonary artery smooth muscle cells (PASMCs). In vitro, MSC-NVs inhibited PDGF-induced proliferation, migration, and phenotype switch of PASMCs. miRNA sequencing analysis of the genetic cargo of MSC-NVs revealed that miR-125b-5p and miR-100-5p are highly abundant, suggesting they might account for the therapeutic effects of MSC-NVs in PH. Depletion of miR-125b-5p and miR-100-5p in MSCs almost completely abolished the beneficial effects of MSC-NVs in protecting PASMCs from PDGF stimulated changes in vitro, and also diminished the protective effects of MSC-NVs in MCT induced PH in vivo. These data highlight the efficacy and advantages of MSC-NVs over MSC-EVs as a promising therapeutic strategy against PH.
Exploring new avenues for clinical management of chronic wounds holds the key to eliminating socioeconomic burdens and health-related concerns associated with this silent killer. Engineered biomaterials offer great promise for repair and regeneration of chronic wounds because of their ability to deliver therapeutics, protect the wound environment, and support the skin matrices to facilitate tissue growth. This mini review presents recent advances in biomaterial functionalities for enhancing wound healing and demonstrates a move from sub-optimal methods to multi-functionalized treatment approaches. In this context, we discuss the recently reported biomaterial characteristics such as bioadhesiveness, antimicrobial properties, proangiogenic attributes, and anti-inflammatory properties that promote chronic wound healing. In addition, we highlight the necessary mechanical and mass transport properties of such biomaterials. Then, we discuss the characteristic properties of various biomaterial templates, including hydrogels, cryogels, nanomaterials, and biomolecule-functionalized materials. These biomaterials can be microfabricated into various structures, including smart patches, microneedles, electrospun scaffolds, and 3D-bioprinted structures, to advance the field of biomaterial scaffolds for effective wound healing. Finally, we provide an outlook on the future while emphasizing the need for their detailed functional behaviour and inflammatory response studies in a complex in vivo environment for superior clinical outcomes and reduced regulatory hurdles.
Extracellular vehicles have a natural targeting ability and immune tolerance of being usually applied in drug delivery systems; however, the purification of EVs is complicated and the production yield was quite low. We developed an artificial cellular mimetic nanovesicle (NV) with melanoma fragment membrane for the transportation with curcumin to achieve the anticancer purpose. B16F10 derived NVs were manufactured by the breakdown of cells using a series of extrusions through cut-off size filters (10 and 5 µm), and the whole procedure was easy and time-saving. To terminate the suspicion of cancer metastatic issue, B16F10 cells were treated by 30-min sonication and 1-min UVB exposure to remove genetic materials before the extrusion. B16F10 derived NV loaded with curcumin was called NV(S30U1/Cur), and the anticancer effect was evaluated by cell-based viability, immune, migration, and invasion. The results showed that NVs were manufactured by passing through 10 and 5 µm filters having an enviable production yield, and the mRNA amounts were declined within NVs produced by B16F10 cells treated with UVB in a comparison to the control group. NV(S30U1/Cur) were effectively decreased B1610 cell viability, and migratory and invasive abilities were also reduced significantly. Besides, CD8⁺ expression of murine primary lymphocytes was activated with CD4⁺ reduction by NV(S30U1/Cur) to stimulate the inherent tumor suppressive capacity in the immune system. Taken together, we established bioengineered NVs serving as novel cell mimetic nanocarriers to deliver natural compound for malignant melanoma potential immune chemotherapy.
Data Availability Statement
The data used to support the findings of this study are available from the corresponding author upon requests.
Exosomes are extracellular vesicles 15 to 150 nm in size and serve as delivery vehicles for long-distance inter-cellular communication. Exosomes contain various biomolecules derived from the cell cytosol and have potential applications in disease diagnosis and drug delivery. However, due to their low density, small size, and scarcity, reliable methods for the selective capture or efficient isolation of exosomes are required to broaden their range of applications. Particularly, the conventional method for selective exosome capture is based on a ligand-receptor interaction using a receptor that targets tetraspanin on the exosome surface. Sensing platforms detect the signal generated by the binding ligand in the sensing region; therefore, efficient exosome capture in a receptor-based exosome sensor platform has a significant impact on the detection performance. The conducting polymer polydiacetylene (PDA) has unique optical properties resulting from the polymerization of self-assembled diacetylene molecules, and PDA based platform can be used to indicate the degree of ligand-receptor interaction. When the PDA backbone is disturbed by an external stimulus, it produces a blue to red colorimetric transition and fluoresces in the red region without a label. Herein, it was confirmed that exosomes were more efficiently captured by a multi-target platform compared to a single-target platform. The PDA array platform demonstrated significantly improved exosome binding efficiency with a 4 to 8-fold increase in sensitivity compared to the single-target system. Moreover, the binding efficiency was high in low exosome concentration environments. Therefore, the multi-target exosome platform increases detection sensitivity through efficient exosome capture and this strategy can be universally applied to applications that use exosome-targeting receptors.
Many properties of nanoparticles are governed by their shape, size, polydispersity and surface chemistry. To apply nanoparticles in chemical sensing, medical diagnostics, catalysis, thermoelectrics, photovoltaics or pharmaceutics, they have to be synthesized with precisely controlled characteristics. This is a time-consuming, laborious and resource-intensive task, because nanoparticle syntheses often include multiple reagents and are conducted under interdependent experimental conditions. Machine learning (ML) offers a promising tool for the accelerated development of efficient protocols for nanoparticle synthesis and, potentially, for the synthesis of new types of nanoparticles. In this Review, we discuss ML algorithms that can be used for nanoparticle synthesis and highlight key approaches for the collection of large datasets. We examine ML-guided synthesis of semiconductor, metal, carbon-based and polymeric nanoparticles, and conclude with a discussion of current limitations, advantages and perspectives in the development of ML-assisted nanoparticle synthesis. Machine learning can be applied for the controlled synthesis of nanoparticles with precise properties. This Review discusses different machine learning approaches for the synthesis of semiconductor, metal, carbon-based and polymeric nanoparticles, and highlights key approaches for the collection of large datasets.
Exploring a rational delivery system of integrating chemotherapy with immunotherapy to broaden benefits of cancer immunochemotherapy is still under challenge. Herein, we developed doxorubicin (DOX)-loaded biomimetic hybrid nanovesicles (DOX@LINV) via fusing artificial liposomes (LIPs) with tumor-derived nanovesicles (TNVs) for combinational immunochemotherapy. DOX@LINV with a homologous targeting ability could deliver DOX to tumor tissue and elicit an effective immunogenic cell death response to improve the immunogenicity of a tumor. Meanwhile, the preserved tumor antigens and endogenous danger signals in DOX@LINV activated dendritic cells and induced a subsequent antigen-specific T cell immune response. DOX@LINV displayed a specific antitumor effect on murine melanoma, Lewis lung cancer, and 4T1 breast cancer based on the infiltration of effector immune cells and improvement of the immunosuppressive tumor microenvironment. Furthermore, the combination of DOX@LINV with immune checkpoint inhibitor amplified antitumor efficacy with 33.3% of the mice being tumor-free. Therefore, the hybrid LINV is a promising drug delivery platform with a boosted antitumor immune response for effective immunochemotherapy.
Ethosomes are widely applied as the carriers for the transdermal delivery of hydrophobic and hydrophilic drugs. Herein, curcumin-loaded ethosomes (CE) with different phospholipid composition were formulated and thoroughly compared. A significant interaction between the unsaturated phosphatidylcholine (PC) and saturated hydrogenated phosphatidylcholine (HPC) was found by molecular simulation and differential scanning calorimetry (DSC), which led to the reduction of PC peroxidation with the presence of HPC. Subsequently, the composite phospholipid ethosomes containing curcumin were prepared for the first time to evaluate their properties in comparison with the conventional ethosomes composed of PC (CE-P) or HPC (CE-H). CE with PC/HPC ratio of 1:1 (CE-P1H1) with the best vesicle stability and flexibility significantly decreased the uptake by HaCaT cells compared to CE-H and free curcumin, indicating reduced skin cell toxicity. Compared with free curcumin, CE-P1H1 had the highest transdermal efficiency (p < 0.001), followed by CE-P (p < 0.05), partly due to the fact that CE-P1H1 could disturb lipid domain of stratum corneum (SC). Moreover, CE-P1H1 was found to promote curcumin for deep penetration of the skin via the hair follicles route. Our study has shown that using composite phospholipid ethosomes as lipid vesicular carriers could enhance transdermal penetration of drugs and increase in the vesicle stability.
Prevailing drug delivery strategies rely on the use of synthetic nanocarriers like metal nanoparticles and polymeric liposomes to control the release of therapeutics in a safe and efficacious manner. Despite their high efficiency in encapsulating drugs, these systems exhibit low to moderate biocompatibility, low cellular uptake, and sub-optimal targeting capabilities. Conversely, cell-derived nanoparticles (CDNs) have emerged as a promising alternative to these artificial drug delivery carriers for achieving safer clinical outcomes. In this study, we have generated CDNs from human adipose-derived stem cells (hASCs) using a high-yield fabrication strategy. Briefly, hASCs were subjected to a cell-shearing approach that entails passing the cells through an array of filters, along with serial centrifugations to eliminate intracellular contents. Ultimately, the fragmented parent cell membrane self-assembles to form the CDNs. This strategy successfully converted 80% of the plasma membrane into the novel nanocarriers with an average hydrodynamic diameter of 100 nm. Stability analysis confirmed that the formulated nanocarriers are stable for over 3 weeks, making them a potent candidate for long-term therapies. To demonstrate their potential in drug delivery, we encapsulated trehalose, a cell-impermeable sugar molecule, into the CDNs via an extrusion loading technique. Drug-loaded CDNs were effectively internalized into human umbilical vein endothelial cells (HUVECs) and hASCs, without inducing any significant cytotoxicity. Overall, the findings of this study establish the potential of hASC-derived CDNs as customizable biomimetic nanocarriers for drug delivery and other translational medicine applications.
Virus-like particles (VLPs) are empty (genome-free) shells of a virus which have similar or indistinguishable structures to the original virus. As a result, they are non-pathogenic but can mimic the viral surface. This in combination with their size makes them a highly immunogenic and a safe vaccine candidate. Furthermore, the structure of the particles can be modified to display antigens and/or VLPs can be loaded with different molecules. Here we give an overview about the use of VLPs as vaccines and as nano carriers. We describe their properties, compare VLP production platforms and discuss modification possibilities and strategies.
The therapeutic efficacy of current cancer vaccines is far from optimal, mainly because of insufficient induction of antigen-specific T cells and because tumor cells can hijack immunosuppressive mechanisms to evade the immune responses. Generating specific, robust, and long-term immune responses against cancer cells and the attenuating of immunosuppressive factors are critical for effective cancer vaccination. Recently, the engineering of exosomes specifically bind to T cells, and then stimulating tumor-specific T-cell immune responses has emerged as a potential alternative strategy for cancer vaccination. In this study, we generated a bifunctional exosome combining the strategy of vaccination and checkpoint blockade. Exosomes prepared from Ovalbumin (OVA)-pulsed, activated dendritic cells were modified with anti-CTLA-4 antibody (EXO-OVA-mAb) to block this inhibitory molecule and to enhance the specificity of the exosomes toward T cells. Our study provides a unique strategy for functionalizing exosome membrane with anti-CTLA-4 antibody via lipid-anchoring method to synergize efficacy of cancer vaccination and immune checkpoint blockade against the tumor.
Statement of Significance
We designed T-cell-targeting exosomes (EXO-OVA-mAb) decorated with costimulatory molecules, MHCs, antigenic OVA peptide, and anti-CTLA-4 antibody, combining the strategies of vaccines and checkpoint blockade. The exosomes showed enhanced binding to T cells in tumor-draining lymph nodes, effectively induced T-cell activation, and improved the tumor homing of effector T cells, ultimately significantly restraining tumor growth. Thus, EXO-OVA-mAb greatly facilitates T-cell targeting, induces a strong tumor-specific T-cell response, and increased the ratio of effector T cells/regulatory T cells within tumors, resulting in appreciable tumor growth inhibition.
We report cellular nanosponges as an effective medical countermeasure to the SARS-CoV-2 virus. Two types of cellular nanosponges are made of the plasma membranes derived from human lung epithelial type II cells or human macrophages. These nanosponges display the same protein receptors, both identified and unidentified, required by SARS-CoV-2 for cellular entry. It is shown that, following incubation with the nanosponges, SARS-CoV-2 is neutralized and unable to infect cells. Crucially, the nanosponge platform is agnostic to viral mutations and potentially viral species, as well. As long as the target of the virus remains the identified host cell, the nanosponges will be able to neutralize the virus.
