Enhanced Local Delivery of Engineered IL-2 mRNA by Porous Silica Nanoparticles to Promote Effective Antitumor Immunity

Localized expression of immunomodulatory molecules can stimulate immune responses against tumors in the tumor microenvironment while avoiding toxicities associated with systemic administration. In this study, we developed a polyethylenimine-modified porous silica nanoparticle (PPSN)-based delivery platform carrying cytokine mRNA for local immunotherapy in vivo. Our delivery platform was significantly more efficient than FDA-approved lipid nanoparticles for localized mRNA translation. We observed no off-target translation of mRNA in any organs and no evidence of systemic toxicity. Intratumoral injection of cytokine mRNA-loaded PPSNs led to high-level expression of protein within the tumor and stimulated immunogenic cancer cell death. Additionally, combining cytokine mRNA with an immune checkpoint inhibitor enhanced anticancer responses in several murine cancer models and enabled the inhibition of distant metastatic tumors. Our results demonstrate the potential of PPSNs-mediated mRNA delivery as a specific, effective, and safe platform for mRNA-based therapeutics in cancer immunotherapy.