Dual-action endoplasmic reticulum membrane-fusogenic immunogenic liposomes amplify cellular immunity in anti-tumor vaccine design.

Adjuvants are critical for amplifying vaccine efficacy, yet conventional formulations (e.g., aluminum salts, MF59) predominantly elicit humoral immunity and fail to induce robust CD8+ T cell responses, which are essential for combating cancer. While nanoscale lipid delivery systems improve lymph node targeting and co-delivery, their capacity to drive potent cellular immunity remains limited. Here, we introduce a distinct design of phosphatidylinositol-based immunomodulatory nanoliposomes (PI-INLs) that uniquely synergize endogenous adjuvant activity with membrane-fusogenic properties to overcome this barrier. Unlike synthetic nano-adjuvants that rely on exogenous immunostimulants, PI-INLs leverage rationally assembled natural phospholipids to function dually: (1) as an intrinsic adjuvant that activates antigen-presenting cells via the GPCR-PLC-IP₃/Ca2+ signaling cascade; and (2) as a membrane-fusogenic system that directly delivers antigens to the endoplasmic reticulum (ER), the central hub for MHC-I antigen processing. This dual mechanism ensures simultaneous activation of innate immune signaling and enhancement of antigen cross-presentation. In murine tumor prophylaxis models, ovalbumin (OVA)-loaded PI-INLs elicited substantially stronger CD8+ T cell responses and conferred superior tumor protection and treatment compared to MF59-adjuvanted OVA. Our work establishes an applicable paradigm for self-adjuvanting nanovaccines, demonstrating that rational exploitation of natural phospholipid assemblies can achieve potent, coordinated cellular immunity.