Viral nanoparticles for drug delivery, imaging, immunotherapy, and theranostic applications

Abstract

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.

Keywords: Bacteriophages; Cancer; Chemotherapy; Contrast agents; Drug delivery systems; Infectious disease; Plant viruses; Theranostics; Vaccine.

Graphical abstract

Fig. 1

Different plant VLPs and bacteriophages to scale. CCMV (PDB ID: 1ZA7), CPMV (PDB ID: 1NY7), PhMV (PDB ID: 1QJZ), SeMV (PDB ID: 1X33), TMV (PDB ID: 2TMV), MS2 (1AQ3), Qβ (PDB ID: 5KIP), and P22 (PDB ID: 5UU5) and images were reconstructed using UCSF Chimera software.

Fig. 2

Strategies to carry cargo using VLPs include: a) self-assembly around cargo by altering pH and buffer conditions with CCMV, b) infusion of cargo within RCNMV due to changes in pH and salt concentrations, c) genetic engineering techniques utilizing genetically conjugated scaffolding proteins to encapsulate drugs within P22, d) bioconjugation onto CPMV using exterior surface-exposed residues.

Fig. 3

Various VLPs and their incorporation of DOX through infusion, bioconjugation, adsorption, and using polymerization chemistries a) Infusion and surface binding of DOX onto RCNMV VLPs in different buffers to study the binding and release characteristics of DOX from the nanoparticles (reproduced with permission from ref [34]) b) Bioconjugation of DOX-N-ε-maleimidocaproic acid hydrazides onto TMV disk VLPs through maleimide linkages to the cysteine residues (reproduced with permission from ref [36]) c) Adsorption of DOX onto the exterior surface of PVX (reproduced with permission from ref [40]) d) Copper-catalyzed azide-alkyne cycloaddition of DOX onto OEGMA-N₃-polymerized Qβ (reproduced with permission from ref [47]).

Fig. 4

Different mechanisms of loading platinum-based drugs such as phenPt and cisplatin into TMV a) Graphical abstract from Lippard, S.J., et al. showing the loading schematic for phenPt loading into wild-type TMV particles (reproduced with permission from ref [50]) b) Graphical illustration of the phenPt docking onto the Glu97 and Glu106 residues of TMV as discovered through matrix-assisted laser desorption/ionization – mass spectrometry and nuclear magnetic resonance spectroscopy c) Graphical schematic of the assembly of TMV spherical nanoparticles using a fluorous ponytail interaction (F-TMVCP). Cisplatin was loaded into the F-TMVCP using the same glutamic residues as in b (not shown) (reproduced with permission from ref [52]).

Fig. 5

Overall mechanism of VLP in situ vaccination in treating solid tumors: 1) the VLP is delivered directly into the tumor, 2) the VLP is taken up by neutrophils, which become activated and release chemokines, 3) neutrophils activated by the released chemokines infiltrate the tumor and release more chemokines, 4) T-lymphocytes become activated leading to tumor lysis, 5) activated T-lymphocytes travel systemically throughout the body, 6) T-lymphocytes attack metastatic tumors throughout the body.

Fig. 6

Mechanism of action of different viral vaccine candidates. Subunit vaccines (bottom left) can be of two different types: 1) encapsulating the antigenic subunit and 2) displaying the subunit on the exterior. VLP vaccines (bottom center) mimic the natural virus, but are devoid of their genome thus disabling replication. Their capsids are still decorated with the antigens displayed by the APC. Viral vector vaccines can be replicating (top center) or non-replicating (not shown). Viral vector vaccines contain the genomic information for the necessary antigens within their own genomes. Cell entry leads to genomic processing leading to the display of the encoded antigens on the cell surface. The replication machinery remains intact for replicating viral vector vaccines producing more of the viral vaccines, which goes on to infect other APCs. The steps highlighted in red are those taken by the subunit and VLP vaccines. The steps highlighted in blue are those taken by the viral vector vaccine. Those in purple are steps taken by the subunit, VLP, and viral vector vaccines. The antigens are displayed on the cell surfaces priming both CD4+ and CD8+ T-cells. The CD4+ T-cells go on to activate B-cells, which secrete antibodies. Activated CD8+ T-cells induce a CTL response. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 7

Different modalities that VLPs can be used in for imaging and theranostics. The gray circles represent imaging modalities mainly used in preclinical settings (e.g. animal studies) or those that are in development for the clinic. The circles in purple represent imaging modalities utilized in the clinic.

Fig. 8

Bubble diagram of the proposed drug delivery and imaging/theranostic platforms discussed in this review by plant viruses, bacteriophages, mammalian viruses, and protein cages.