Facile manganese ion-coordination assembly of nanogels for synergistic cancer chemo–chemodynamic-immunotherapy

Metal-ion therapy is an emerging technique for cancer treatment, where anticancer metals trigger an immune response against tumor cells due to immunogenic cell death while enabling chemokinetic therapy, and the integration of these activities holds considerable anticancer potential for achieving high specificity and efficiency. Herein, we designed acid-responsive manganese-based nanogels with high drug-loading capacity for combined chemotherapy, chemodynamic therapy, and metal-immune therapy. The chemotherapeutic drug mitoxantrone, metallic manganese ions, and polymeric polyacrylic acid self-assembled into stable nanogels that could be efficiently internalized by cancer cells efficiently, releasing Mn2+ to catalyze highly toxic of hydroxyl generation from endogenous H2O2 and induce tumor cell apoptosis. Furthermore, the Mn2+-mediated activation of cyclic guanosine monophosphate adenosine synthetase activated the stimulator of interferon genes (STING) pathway, thereby inducing dendritic cell maturation. Following intravenous injection into immunocompetent tumor-bearing mice, the nanogels effectively exerted a tumor-killing effect and enhanced the antitumor immune response in combination with an aCTLA-4 antibody. Manganese ions also enhanced T1-weighted magnetic resonance imaging for integrated diagnosis and treatment. Overall, the manganese-based nanogel demonstrates significant synergistic efficacy through combined chemotherapy, chemodynamic therapy and metal-immune therapy, providing a versatile therapeutic strategy for cancer treatment.