Hybrid nanovesicle artificial antigen-presenting cells integrate endogenous tumor antigen display with senescence-mimetic erythrocyte membrane-directed splenic T-cell priming.

Artificial antigen-presenting cells (aAPCs) provide a non-genetic approach to T-cell activation, but their in vivo performance is often limited by predefined peptide-major histocompatibility complex class I (pMHC-I) repertoires and inefficient delivery to secondary lymphoid organs. Here, we engineer senescence-derived hybrid nanovesicles that integrate endogenous antigen display and organ-directed trafficking within a single membrane material. Nanovesicles derived from senescent cancer cells retain increased levels of endogenously generated pMHC-I complexes, whereas nanovesicles derived from senescence-mimetic red blood cells confer spleen-directed biodistribution. Fusion of these membranes generates SS-hNVs, which are further functionalized with anti-CD28 and interleukin-2 to form SS-aAPCs that provide coordinated T-cell receptor (TCR), costimulatory, and cytokine signals. Hybrid membrane composition governs splenic accumulation and CD8+ T-cell engagement following intravenous administration. SS-aAPCs expand antigen-specific CD8+ T cells and TCF-1+PD-1+ progenitor-like populations, enhance cytotoxic responses, and suppress tumor growth in B16-OVA and MC38 models. Combination with programmed death-ligand 1 (PD-L1) blockade further improves tumor control. By assigning endogenous antigen display and lymphoid trafficking to distinct source membranes, this platform establishes a structure-function strategy for constructing systemically administered aAPCs. These findings support that physiologically remodeled membranes can be assembled as modular biomaterials to coordinate molecular immune signaling with organ-level biodistribution, enabling in vivo T-cell priming without predefined epitope loading or genetic modification of immune cells.