A cascade-regulated nanoadjuvant for antigen oxidation and capture to potentiate in-situ cancer vaccination

In-situ cancer vaccination exhibits poor correlation between antigen release and immune responses, as released antigens disperse rapidly before sustained immune cell engagement. We hypothesized that covalent antigen capture could overcome this limitation by converting transient antigen exposure into durable immune stimulation. Here, we developed DL/CDC, a nanoadjuvant that selectively oxidizes tumor antigens and then captures them via sulfenic acid chemistry. DL/CDC depletes intracellular glutathione by over 50 % via Michael addition, thereby disrupting redox homeostasis and amplifying oxidative stress. This oxidative environment converts protein thiol groups to sulfenic acids on tumor antigens. Surface-conjugated diketone groups then covalently immobilize these sulfenylated antigens through nucleophilic addition, achieving a capture capacity of approximately 500 μg protein per mg DL/CDC. This covalent capture mechanism sustains antigen retention at tumor sites 7-fold higher than free antigens at 24 h and enhances lymph node delivery 3-fold, amplifying dendritic cell maturation 4.8-fold and CD8⁺ Tcell infiltration 6-fold. Combined with photothermal therapy, DL/CDC achieved 67 % long-term survival with durable immune memory.