A Structurally Stabilized Lipopolymer Nanoplatform Targeting Pan‐Tissue Antigen‐Presenting Cells Enables Durable in situ mRNA Cancer Immunotherapy

Abstract

ABSTRACT Messenger RNA (mRNA) vaccines have transformed cancer immunotherapy, yet delayed immune activation, multi‐dose requirements, and poor efficacy in immunosuppressive tumor microenvironments (TMEs) hinder current platforms. Here, a structurally stabilized lipopolymer nanoparticle (LPNP) platform is proposed for in situ mRNA vaccination targeting antigen‐presenting cells (APCs). Central to this system is a rationally engineered double‐branched lipopolymer, P6CIT, whose unique molecular architecture enhances hydrophobic microviscosity and intermolecular packing, increasing particle rigidity and preventing premature disassembly in biological fluids. This stabilization enhances circulation stability and promotes favorable biodistribution to tumor sites and lymphoid organs, resulting in a 6.9‐fold increase in the spleen and a 13.6‐fold increase in lymph nodes, key sites for adaptive immune activation. Upon intratumoral administration, the LPNP co‐delivers mRNAs encoding tumor antigens and IL‐12, synergistically reprogramming the TMEs and amplifying APC‐mediated T cell priming. In situ vaccination achieves a 42% complete response in a B16‐OVA melanoma model and outperforms ALC‐0315 LNPs in wild‐type B16F10 tumors. This work highlights chemical‐level structural optimization enabling potent, simplified mRNA immunotherapy.