Nanocatalytic Innate Immunity Activation by Mitochondrial DNA Oxidative Damage for Tumor‐Specific Therapy

Abstract The innate immune system plays a key role in protecting the human body from tumors, which, unfortunately, is largely counteracted by their immune‐suppression function. Such an immune suppression has been reported to be induced by the immunosuppressive microenvironment, including the exhausted cytotoxic T lymphocytes (CTLs) and tumor‐promoting M2‐polarized macrophages. Here, a novel tumor‐immunotherapeutic modality based on the nanocatalytic innate immunity activation by tumor‐specific mitochondrial DNA (mtDNA) oxidative damage is proposed. In detail, a nanocatalytic medicine, Fe²⁺–Ru²⁺‐loaded mesoporous silica nanoparticle named as MSN‐Ru²⁺/Fe²⁺ (MRF), is constructed to induce oxidative damage in the mtDNA of tumor cells. Such an oxidative mtDNA is able to escape from the tumor cells and acts as an immunogenic damage‐associated molecular pattern to M1‐polarize tumor‐associated macrophages (TAMs), resulting in the reactivated immunoresponse of macrophages against cancer cells, and the subsequent inflammatory response of innate immunity. Most importantly, the treatment strategy based on regulating the innate immune response of TAMs not only stops the primary tumor progression, but also almost completely inhibits the growth of distant tumors in the periods of treatments.