Active Microneedle Administration of Plant Virus Nanoparticles for Cancer In Situ Vaccination Improves Immunotherapeutic Efficacy

Abstract

The solid tumor microenvironment (TME) poses a significant structural and biochemical barrier to immunotherapeutic agents. To address the limitations of tumor penetration and distribution and to enhance antitumor efficacy of immunotherapeutics, we present here an autonomous active microneedle (MN) system for the direct intratumoral (IT) delivery of a potent immunoadjuvant, cowpea mosaic virus nanoparticles (CPMV), in vivo. In this active delivery system, magnesium (Mg) microparticles embedded into active MNs react with the interstitial fluid in the TME, generating a propulsive force to drive the nanoparticle payload into the tumor. Active delivery of the CPMV payload into B16F10 melanomas in vivo demonstrated substantially more pronounced tumor regression and prolonged survival of tumor-bearing mice compared to that of passive MNs and conventional needle injection. Active MN administration of CPMV also enhanced local innate and systemic adaptive antitumor immunity. Our approach represents an elaboration of conventional CPMV in situ vaccination, highlighting substantial immune-mediated antitumor effects and improved therapeutic efficacy that can be achieved through CPMV in situ vaccination mediated by an active and autonomous delivery system.

Trivalent Subunit Vaccine Candidates for COVID-19 and Their Delivery Devices

“… 5 , 6 , 11 CPMV and Qβ have high thermal stability and therefore can undergo hot-melt extrusion to formulate slow-release polymer blends as well as fast-soluble microneedle delivery devices. 12 − 14 We adapted these methods to produce COVID-19 vaccine candidates and their delivery devices. Molecular farming of CPMV, fermentation of Qβ, hot melt extrusion of polymer blends, and microneedle (MN) polymer micromolding are scalable techniques and therefore suitable approaches for the development of novel vaccine platform technologies.…”

Microneedle arrays integrated with living organisms for smart biomedical applications

“…Considering that MNAs can easily penetrate the skin, a combination of virus and MNAs to treat melanoma was implemented by Wang et al . ( Figure 3 B ) 63 . They directly delivered cowpea mosaic virus (CPMV) intratumorally by MNA assisted by Mg nanoparticles, significantly suppressing canine melanoma in mice models.…”

“…(iii) Tumor growth of melanoma on mice could be effectively suppressed, mainly by (iv) CPMV-induced in situ vaccination via enhancement of intratumor recruitment and activation of live CD45 + cells. Reproduced with permissions from American Chemical Society 2020 63 .…”

Microneedles for painless transdermal immunotherapeutic applications

“…developed an autonomous active MN for the direct transportation of cowpea mosaic virus NPs (CPMV) as potent immunoadjuvants towards the treatment of B16F10 melanoma in mice [124].…”