A Polymeric mRNA Vaccine Featuring Enhanced Site‐Specific mRNA Delivery and Inherent STING‐Stimulating Performance for Tumor Immunotherapy

Abstract The development of mRNA delivery carriers with innate immune stimulation functions has emerged as a focal point in the field of mRNA vaccines. Nonetheless, the expression of mRNA in specific sites and innate immune stimulation at specific sites are prerequisites for ensuring the safety of mRNA vaccines. Based on the synthetic PEIRs carriers library, this study identifies an innovative mRNA delivery carrier named POctS with the following characteristics: 1) simultaneously possessing high mRNA delivery efficiency and stimulator of interferon genes (STING) stimulation function. 2) Leveraging the distinctive site‐specific delivery capabilities of POctS, the expression of mRNA at specific sites and the activation of innate immune responses at designated sites are achieved, minimizing formulation toxicity and maximizing the vaccine performance. 3) Tailoring two types of mRNA vaccines based on POctS according to the immune infiltration status of different types of tumors. Briefly, POctS‐loading ovalbumin (OVA) mRNA as a tumor antigen vaccine achieves the prevention and treatment of melanoma in mice. Further, POctS‐loading mixed lineage kinase domain‐like protein (MLKL) mRNA as an in situ tumor vaccine effectively treats orthotopic pancreatic cancer in mice. This delivery carrier offers a feasible mRNA vaccine‐based immunotherapy strategy for various types of tumors.