Cyclic D/L-peptides based nanoparticles regulates dendritic cell maturation and enhances anti-tumor immune response

Immunotherapy offers enduring cancer treatment by activating the immune system to eliminate cancer cells, but faces challenges like tumor immune evasion and low immunogenicity. Chirality, crucial in biological interactions, remains underexplored for immune modulation. Inspired by the metal-binding domain of manganese superoxide dismutase, we develop a cyclic D/L peptide for chirality-driven immune activation. The cyclic L -Tyr- D -His- L -Asp- D -His (YhDh) peptide coordinates with Mn 2+ to self-assemble into nanoparticles, cloak with tumor cell membranes for homologous targeting. Compared to all-L or all-D peptides, YhDh nanoparticles promote costimulatory molecule expression on dendritic cells (DCs). Upon intravenous administration, they are oxidized at melanoma sites with tyrosinase overexpression, enabling photothermal-induced immunogenic cell death (ICD). Chiral peptides synergize with Mn 2+ -mediated cGAS-STING activation and ICD, enhancing DC maturation and T cell infiltration (4.36- and 2.88-fold), suppressing tumor metastasis while establishing immune memory. Such chiral cyclic peptides offer a novel strategy for immune activation by regulating peptide chirality.