STING Agonist-Loaded Physalis Mottle Virus-like Particles as a Potent Prophylactic for Metastatic Melanoma

Abstract

Stimulator of interferon genes (STING) agonists have been presented as a compelling cancer therapeutic for many years yet have been unable to break past clinical trials. To date, the best use cases for STING agonists are as intratumoral therapeutics for solid tumors, but in human trials, rapid wash-out and low efficacy hamper success. Systemic administrations of STING agonists have also been explored, but hurdles include enzymatic instability, leading to rapid clearance and immune toxicity. To overcome these challenges, nanoparticle delivery technologies have been proposed, and in the present study, we bioconjugated a STING agonist to the internal cavity of Physalis mottle virus (PhMV)-like nanoparticles (termed PhMV-STG). PhMV-STG demonstrated enhanced and extended interferon activity in vitro as well as prolonged tumor retention in vivo. Intratumorally applied PhMV-STG sustained similar antitumor efficacy as free STG. As a new direction, we also demonstrate the potential of PhMV-STG as a prophylaxis for outgrowth of metastatic lung nodules from solid tumors. A single systemic injection of PhMV-STG prevented the formation of melanoma lung metastases, in stark contrast to the lack of prevention by free STG. Overall, these findings present a compelling argument to use virus-like particles to improve the function of STING agonists as well as a path forward to elucidate the mechanism behind its success as a cancer prophylactic.

Keywords: Physalis mottle virus (PhMV); cancer immunotherapy; cancer prophylaxis; melanoma; metastatic cancer; stimulator of interferon genes (STING); virus-like particles (VLPs).