Catalytic HybridLipid Nanoparticles Potentiate CircleRNA-Based Cytokine Immunotherapy

Cytokine therapeutics in cancer immunotherapy are greatly limited by their short half-time, serious toxicity, and frequent administration, which can possibly be addressed by ribonucleic acid (RNA) technology through the expression of targeting cytokines in situ. However, the intracellular translation of RNA remains restricted due to the generation of excessive reactive oxygen species (ROS) and overconsumption of adenosine triphosphate (ATP) within the transfected cells. Herein, hybrid lipid nanoparticles (Mn-LNPs) are developed by incorporating small-sized trimanganese tetraoxide nanoparticles within conventional lipid nanoparticles, showing the ability to generate oxygen, eliminate ROS, and boost intracellular ATP, thus greatly enhancing the translation efficiency. This hybrid platform is employed to encapsulate interleukin 12 (IL-12)-encoding circular RNA (Mn-LNPs@RNA^IL‑12) for tumor immunotherapy, exhibiting unparalleled advantages in the proliferation of cytotoxic T cells and stimulation of antitumor immunity. Moreover, the antitumor efficacy of Mn-LNPs@RNA^IL‑12 is further strengthened by synergizing with immune checkpoint blockade therapy to achieve durable and potent antitumor performances.