Multifunctional hybrid oncolytic virus-mimicking nanoparticles for targeted induce of tumor-specific pyroptosis and enhanced anti-tumor immune response in melanoma

Pyroptosis, a newly discovered form of programmed cell death, has emerged as a promising antitumor approach by releasing pro-inflammatory cytokines and immunogenic substances upon cell rupture. However, non-specific pyroptosis potentially causes systemic damage to healthy tissues, and the heterogeneity of tumors limits the antitumor effect of pyroptosis. To address these challenges, we propose a simple yet powerful method for creating multifunctional hybrid oncolytic virus-mimicking nanovesicles (HVMNVs) that possess tumor-targeting capabilities, adjuvant activity, and the ability to evade immune clearance induced by virus modification. Based on this multifunctional nanovesicle, we developed a functional nanoparticle (HVMNVs@Fe-C) that significantly enhances the tumor targetability and cell uptake efficiency of the extremely small iron oxide nanoparticles (ESIONPs) and carbonyl cyanide m-chlorophenyl hydrazone (CCCP), leading to rapid tumor pyroptosis. More importantly, HVMNVs@Fe-C ingeniously achieves a synergistic effect by incorporating the adjuvantic and tumor-targeting properties of oncolytic viruses with the cell lytic and pro-inflammatory functions of pyroptosis in a single nanoparticle. This leads to a cascade of specific anti-tumor immune responses and reprogramming of the immunosuppressive tumor microenvironment, resulting in excellent tumor inhibition efficacy against primary melanoma growth and pulmonary metastasis. Overall, our novel strategy offers considerable promise for precisive targeted delivery and cancer immunotherapy.