循环RNA编码的二聚体IL-15前药的肿瘤靶向递送可增强新抗原疫苗的疗效

Abstract

Cytokine-based immunotherapy, exemplified by interleukin-15 (IL-15), holds promise for reinvigorating antitumor immunity but is hampered by systemic toxicity and short half-life. Here, we engineered a dimeric IL-15 prodrug (IL15D) with a matrix metalloproteinase-14-cleavable peptide linker to minimize systemic activity, and integrated it within a circular RNA (circRNA) scaffold for sustained expression. This circRNA-encoded prodrug was encapsulated into cyclic RGD (cRGD)-functionalized lipid nanoparticles (LNPs) for tumor-enriched delivery. In murine tumor models, systemic administration of cRGD-CircIL15D-LNPs demonstrated an improved safety profile and robustly remodeled the tumor microenvironment (TME), leading to significant tumor growth inhibition. Crucially, combining tumor-targeted Circ-IL15D with an intramuscular neoantigen mRNA vaccine synergistically amplified tumor-specific T cell immunity, effectively converting immunologically “cold” tumors into “hot” ones. This combination therapy achieved potent suppression of both orthotopic hepatocellular carcinoma and metastatic setting, with complete tumor regression observed in a subset of mice. Overall, our work establishes a versatile platform for the spatially controlled delivery of bioactive cytokines that can synergize with vaccination to potentiate cancer immunotherapy