Reprogramming anti-tumor immunity through both NLRP3 inflammasome and cGAS-STING pathways by chiral nanoadjuvants

Cancer immunotherapy has shown significant promise but faces challenges due to concerns around safety, the complex tumor microenvironment, and the low immunogenicity of cancer vaccines. Here, we report the synthesis of degradable chiral trimanganese tetroxide nanoparticles (Mn₃O₄ NPs) by modifying chiral mannose ligands to create chiral vaccines for cancer therapy and prevention. The L-type Mn₃O₄ nanoparticles (L-NPs) exhibit nearly twice the uptake rate into mouse bone marrow dendritic cells (BMDCs) compared to D-type Mn₃O₄ nanoparticles (D-NPs), thanks to a higher affinity for X-C motif chemokine ligand 1 (XCR1), cluster of differentiation 14 (CD14), and Toll-like receptor 4 (TLR4). When loaded with tumor antigens as vaccines (L-Vac), the L-NPs activate BMDCs through both NOD-like receptor protein 3 (NLRP3) inflammasome and cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathways, enhancing the levels of C-C motif chemokine ligand 5 (CCL5) and reducing C-C motif chemokine ligand 22 (CCL22) expression. Molecular dynamics (MD) simulation explored the lock-and-key mechanism on the chiral NPs distinct patterns of interaction with antigen. Noticeably, the anti-tumor immunity was successfully confirmed in patient-derived xenograft (PDX) mouse model, depicting the clinical potential of chiral vaccines. L-Vac demonstrates high in vivo biosafety, breaking down into manganese ions that are primarily excreted through feces. Therefore, chiral adjuvants will pave a brilliant avenue to facilitate cancer immunotherapy.