A Nitric Oxide–Based STING Agonist Nanoadjuvant With ICD‐Derived Membrane Antigens Unleashes Robust Antitumor Immunity

Despite significant advances in nanovaccine development, their efficacy remains hindered by poor antigen presentation, limited antigen repertoire, and suboptimal T cell priming. Immune adjuvants such as polyinosinic‐polycytidylic acid (POLY(I:C)) exert antitumor effects by promoting dendritic cell (DC) maturation and stimulating innate immunity, but their efficacy is limited by poor antigen presenting cell (APC) uptake and weak CD8 + T cell responses. Here, we propose a novel adjuvant strategy using nitric oxide (NO), a bioactive gaseous molecule, to upregulate MHC‐I and enhance DC cross‐presentation, thereby synergistically improving the adjuvant efficacy of POLY(I:C). We developed a nanovaccine, Im@NOnanoPL, by co‐encapsulating a preassembled complex of DOTAP, NOC‐18, and POLY(I:C) into a PLGA shell, which was further modified with DSPE‐PEG 2000 and camouflaged with immunogenic cell death (ICD)–derived tumor membranes for broad‐spectrum tumor antigen coverage. Im@NOnanoPL elicited robust and durable CD8 + T cell responses, conferring near‐complete prophylactic protection and, in combination with αPD‐1 therapy, eradicating established tumors while inducing long‐term immune memory. Im@NOnanoPL constitutes a novel vaccine platform that integrates a gas‐based adjuvant with broad‐spectrum antigens, exhibiting strong translational potential.