Engineered metallo-albumin nanoscaffolds that target lymph nodes, deliver antigens and activate STING for cancer immunotherapy.

Lymph nodes serve as strategic targets for cancer vaccines by enhancing interactions with antigen-presenting cells (APCs) and promoting immune activation. Herein, we report that serum albumin can be chemically modified via in situ reduction with a short PEG linker, which subsequently coordinates with Mn2+ to generate a lymph nodes targeting metallo-albumin nano-scaffold (MANS) capable of chelating His-tagged antigens and immunostimulatory adjuvants. Maintaining the "hitchhiking" effect of albumin, the MANS chelating antigens (E7 or AH1) accumulates in lymph nodes, where it triggers the responsive release of metal ions and adjuvants to synergistically activate the cGAS-STING pathway. Following uptake by bone marrow dendritic cells (BMDCs), MANS promoted the expression of maturation markers and cytokine release. In multiple murine TC-1 and CT26 tumor models, the MANS vaccine suppresses tumor growth and prolongs survival while elevating antigen-specific CD8+ T cells frequency by an order of magnitude; however, these effects were not observed in STING-knockout mice (STING-KO). The MANS vaccine also remodeled the tumor immune microenvironment (TME) by downregulating immunosuppressive cells in the tumor tissues with long-term immune memory, verified by a tumor rechallenge model.