This review provides an overview of recent developments in "chemical virology." Viruses, as materials, provide unique nanoscale scaffolds that have relevance in chemical biology and nanotechnology, ...with diverse areas of applications. Some fundamental advantages of viruses, compared to synthetically programmed materials, include the highly precise spatial arrangement of their subunits into a diverse array of shapes and sizes and many available avenues for easy and reproducible modification. Here, we will first survey the broad distribution of viruses and various methods for producing virus-based nanoparticles, as well as engineering principles used to impart new functionalities. We will then examine the broad range of applications and implications of virus-based materials, focusing on the medical, biotechnology, and energy sectors. We anticipate that this field will continue to evolve and grow, with exciting new possibilities stemming from advancements in the rational design of virus-based nanomaterials.
Abstract Nanomaterials have been developed for potential applications in biomedicine, such as tissue-specific imaging and drug delivery. There are many different platforms under development, each ...with advantages and disadvantages, but viral nanoparticles (VNPs) are particularly attractive because they are naturally occurring nanomaterials, and as such they are both biocompatible and biodegradable. VNPs can be designed and engineered using both genetic and chemical protocols. The use of VNPs has evolved rapidly since their introduction 20 years ago, encompassing numerous chemistries and modification strategies that allow the functionalization of VNPs with imaging reagents, targeting ligands, and therapeutic molecules. This review discusses recent advances in the design of “smart” targeted VNPs for therapeutic and imaging applications. From the Clinical Editor This review focuses on viral nanoparticles, which are considered attractive naturally occurring nanomaterials due to their inherent biocompatibility and biodegradability. These can be used as imaging reagents, targeting ligands and therapeutic molecules.
Viral nanoparticles (VNPs) encompass a diverse array of naturally occurring nanomaterials derived from plant viruses, bacteriophages, and mammalian viruses. The application and development of VNPs ...and their genome-free versions, the virus-like particles (VLPs), for nanomedicine is a rapidly growing. VLPs can encapsulate a wide range of active ingredients as well as be genetically or chemically conjugated to targeting ligands to achieve tissue specificity. VLPs are manufactured through scalable fermentation or molecular farming, and the materials are biocompatible and biodegradable. These properties have led to a wide range of applications, including cancer therapies, immunotherapies, vaccines, antimicrobial therapies, cardiovascular therapies, gene therapies, as well as imaging and theranostics. The use of VLPs as drug delivery agents is evolving, and sufficient research must continuously be undertaken to translate these therapies to the clinic. This review highlights some of the novel research efforts currently underway in the VNP drug delivery field in achieving this greater goal.
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Oligodeoxynucleotides (ODNs) with CpG motifs have potent immunostimulatory effects on many subsets of immune cells. For example, Class B CpG‐ODNs, such as ODN1826 induce the phagocytic activity of ...macrophages by activating the Toll‐like receptor 9 signaling pathway. Systemic ODN delivery results in unfavorable pharmacokinetic profiles and can trigger adverse effects. To address this issue, plant virus‐like particles (VLPs) are developed for the targeted delivery of ODN1826 to tumor‐associated macrophages (TAMs). ODN1826 is encapsulated by the in vitro disassembly and reassembly of Cowpea chlorotic mottle virus (CCMV), producing VLPs that are structurally analogous to the native virus. The encapsulation of ODN1826 in CCMV‐derived VLPs promotes ODN uptake by TAMs ex vivo and significantly enhance their phagocytic activity. The antitumor activity of the VLPs in vivo is also evaluated, revealing that the direct injection of ODN1826 VLPs into established tumors induces a robust antitumor response by increasing the phagocytic activity of TAMs in the tumor microenvironment. CCMV encapsulation significantly enhances the efficacy of ODN1826 compared to the free drug, slowing tumor growth and prolonging survival in mouse models of colon cancer and melanoma.
CpG oligodeoxynucleotides (ODNs) are efficiently encapsulated by dis‐ and reassembly of cowpea chlorotic mottle virus. Intratumoral administration of CpG‐ODN‐loaded virus‐like particles (VLPs) exhibit higher efficacy to inhibit tumor growth than that by free CpG‐ODNs, indicating the potential of VLPs loaded with CpG‐ODNs for clinical development.
Humanity is experiencing a catastrophic pandemic. SARS-CoV-2 has spread globally to cause significant morbidity and mortality, and there still remain unknowns about the biology and pathology of the ...virus. Even with testing, tracing, and social distancing, many countries are struggling to contain SARS-CoV-2. COVID-19 will only be suppressible when herd immunity develops, either because of an effective vaccine or if the population has been infected and is resistant to reinfection. There is virtually no chance of a return to pre-COVID-19 societal behavior until there is an effective vaccine. Concerted efforts by physicians, academic laboratories, and companies around the world have improved detection and treatment and made promising early steps, developing many vaccine candidates at a pace that has been unmatched for prior diseases. As of August 11, 2020, 28 of these companies have advanced into clinical trials with Moderna, CanSino, the University of Oxford, BioNTech, Sinovac, Sinopharm, Anhui Zhifei Longcom, Inovio, Novavax, Vaxine, Zydus Cadila, Institute of Medical Biology, and the Gamaleya Research Institute having moved beyond their initial safety and immunogenicity studies. This review analyzes these frontrunners in the vaccine development space and delves into their posted results while highlighting the role of the nanotechnologies applied by all the vaccine developers.
Cowpea mosaic virus (CPMV) is a plant virus that has been developed for multiple biomedical and nanotechnology applications, including immunotherapy. Two key platforms are available: virus ...nanoparticles (VNPs) based on the complete CMPV virion, including the genomic RNA, and virus-like nanoparticles (VLPs) based on the empty CPMV (eCPMV) virion. It is unclear whether these platforms differ in terms of immunotherapeutic potential. We therefore compared their physicochemical properties and immunomodulatory activities following
vaccination of an aggressive ovarian tumor mouse model (ID8-Defb29/Vegf-A). In physicochemical terms, CPMV and eCPMV were very similar, and both significantly increased the survival of tumor-bearing mice and showed promising antitumor efficacy. However, they demonstrated distinct yet overlapping immunostimulatory effects due to the presence of virus RNA in wild-type particles, indicating their suitability for different immunotherapeutic strategies. Specifically, we found that the formulations had similar effects on most secreted cytokines and immune cells, but the RNA-containing CPMV particles were uniquely able to boost populations of potent antigen-presenting cells, such as tumor-infiltrating neutrophils and activated dendritic cells. Our results will facilitate the development of CPMV and eCPMV as immunotherapeutic vaccine platforms with tailored responses.
The engagement of antiviral effector responses caused by viral infection is essential when using viruses or virus-like particles (VLPs) as an immunotherapeutic agent. Here, we compare the chemophysical and immunostimulatory properties of wild-type cowpea mosaic virus (CPMV) (RNA containing) and eCPMV (RNA-free VLPs) produced from two expression systems (agrobacterium-based plant expression system and baculovirus-insect cell expression). CPMV and eCPMV could each be developed as novel adjuvants to overcome immunosuppression and thus promote tumor regression in ovarian cancer (and other tumor types). To our knowledge, this is the first study to define the immunotherapeutic differences between CPMV and eCPMV, which is essential for the further development of biomedical applications for plant viruses and the selection of rational combinations of immunomodulatory reagents.
Highlights ► Viral nanoparticles serve as versatile tools for applications in medicine. ► Genetically engineered VNPs are used as vaccines. ► Chemically engineered VNPs are used in targeted ...drug-delivery and biomedical imaging.
Immune checkpoint therapy (ICT) has the potential to treat cancer by removing the immunosuppressive brakes on T cell activity. However, ICT benefits only a subset of patients because most tumors are ...“cold”, with limited pre‐infiltration of effector T cells, poor immunogenicity, and low‐level expression of checkpoint regulators. It has been previously reported that Cowpea mosaic virus (CPMV) promotes the activation of multiple innate immune cells and the secretion of pro‐inflammatory cytokines to induce T cell cytotoxicity, suggesting that immunostimulatory CPMV could potentiate ICT. Here it is shown that in situ vaccination with CPMV increases the expression of checkpoint regulators on Foxp3−CD4+ effector T cells in the tumor microenvironment. It is shown that combined treatment with CPMV and selected checkpoint‐targeting antibodies, specifically anti‐PD‐1 antibodies, or agonistic OX40‐specific antibodies, reduced tumor burden, prolonged survival, and induced tumor antigen‐specific immunologic memory to prevent relapse in three immunocompetent syngeneic mouse tumor models. This study therefore reveals new design principles for plant virus nanoparticles as novel immunotherapeutic adjuvants to elicit robust immune responses against cancer.
In situ vaccination with Cowpea mosaic virus (CPMV) reverses the immunosuppressive state of the tumor microenvironment, increasing the expression of checkpoint regulators on effector T cells, and therefore enabling immune checkpoint therapy (ICT). The combined treatment with CPMV and ICT synergistically reduces tumor burden, and induced tumor antigen‐specific immunologic memory to prevent relapse in three immunocompetent syngeneic mouse tumor models.
The application of nanoparticles for medical purposes has made enormous strides in providing new solutions to health problems. The observation that plant virus-based nanoparticles (VNPs) can be ...repurposed and engineered as smart bio-vehicles for targeted drug delivery and imaging has launched extensive research for improving the therapeutic and diagnostic management of various diseases. There is evidence that VNPs are promising high value nanocarriers with potential for translational development. This is mainly due to their unique features, encompassing structural uniformity, ease of manufacture and functionalization by means of expression, chemical biology and self-assembly. While the development pipeline is moving rapidly, with many reports focusing on engineering and manufacturing aspects to tailor the properties and efficacy of VNPs, fewer studies have focused on gaining insights into the nanotoxicity of this novel platform nanotechnology. Herein, we discuss the pharmacology of VNPs as a function of formulation and route of administration. VNPs are reviewed in the context of their application as therapeutic adjuvants or nanocarrier excipients to initiate, enhance, attenuate or impede the formulation's toxicity. The summary of the data however also underlines the need for meticulous VNP structure-nanotoxicity studies to improve our understanding of their in vivo fates and pharmacological profiles to pave the way for translation of VNP-based formulations into the clinical setting.
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•Plant viruses and their virus-like particles have been recognized as platform technologies for applications in nanomedicine.•Plant virus-based nanoparticles (VNPs) can be repurposed and engineered as smart bio-vehicles for targeted drug delivery and imaging; plant VNPs also find applications in vaccines and immunotherapy.•Given the growing body of data that indicate that plant VNPs are promising high value nanocarriers with potential for translational development, it is critical to gain in-depth understanding of their pharmacology to further advance the field.•The pharmacology of VNPs as a function of formulation and route of administration is discussed; most studies commonly reported no overt toxicity in vitro or in vivo; however, majority of these studies focused on routine cell viability assays as well as histopathological and haematological explorations; with no insights from extensive organ-function investigations.•Data highlight the potential for VNPs to impact disease management and treatment, but also underline the need for meticulous VNP structure-nanotoxicity studies to improve our understanding of their in vivo fates and pharmacological profiles to pave the way for translation of VNPs into the clinic.
Abstract Plant virus-based nanoparticles (VNPs) are a novel class of nanocarriers with unique potential for biomedical applications. VNPs have many advantageous properties such as ease of manufacture ...and high degree of quality control. Their biocompatibility and biodegradability make them an attractive alternative to synthetic nanoparticles (NPs). Nevertheless, as with synthetic NPs, to be successful in drug delivery or imaging, the carriers need to overcome several biological barriers including innate immune recognition. Plasma opsonization can tag (V)NPs for clearance by the mononuclear phagocyte system (MPS), resulting in shortened circulation half lives and non-specific sequestration in non-targeted organs. PEG coatings have been traditionally used to ‘shield’ nanocarriers from immune surveillance. However, due to broad use of PEG in cosmetics and other industries, the prevalence of anti-PEG antibodies has been reported, which may limit the utility of PEGylation in nanomedicine. Alternative strategies are needed to tailor the in vivo properties of (plant virus-based) nanocarriers. We demonstrate the use of serum albumin (SA) as a viable alternative. SA conjugation to tobacco mosaic virus (TMV)-based nanocarriers results in a ‘camouflage’ effect more effective than PEG coatings. SA-‘camouflaged’ TMV particles exhibit decreased antibody recognition, as well as enhanced pharmacokinetics in a Balb/C mouse model. Therefore, SA-coatings may provide an alternative and improved coating technique to yield (plant virus-based) NPs with improved in vivo properties enhancing drug delivery and molecular imaging.
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