A Bi‐Adjuvant Senolytic Nanovaccine Modulating Dendritic Cell Senescence Ameliorates Aging‐Related Metabolic Dysfunction

ABSTRACT Senolytic vaccines hold promise for eliminating senescent cells, but their efficacy is limited by poor seno‐antigen immunogenicity and age‐related dendritic cell (DC) dysfunction. Here, we engineered an active biomaterial‐enabled bi‐adjuvant senolytic nanovaccine (CK5‐GC‐NV) by co‐assembling CpG oligodeoxynucleotide with a fusion protein of the seno‐antigen Gpnmb and a cationic spider silk protein variant (CK5). Beyond antigen delivery, the CK5 scaffold acts as an intrinsic senomodulator associated with the downregulation of mitotic kinases Aurka/b and a concomitant decrease in senescence‐associated PI3K/AKT phosphorylation in DCs. This intervention attenuates aged DC phenotypes, restores antigen cross‐presentation, and synergizes with CpG to elicit potent cytotoxic T‐lymphocyte responses against senescent targets. Across multiple aging mouse models, CK5‐GC‐NV immunization orchestrated targeted clearance of Gpnmb + senescent adipocytes, profoundly ameliorating metabolic dysfunction and extending lifespan. This multifunctional biomaterial platform integrates seno‐antigen immunogenicity enhancement with the restoration of aged DC function, providing a promising proof‐of‐concept for antigen‐directed gerotherapeutics.