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

Abstract

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-PEG₂₀₀₀ 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.