Photodynamic O2 Economizer Encapsulated with DNAzyme for Enhancing Mitochondrial Gene‐Photodynamic Therapy

Emerging research suggests that mitochondrial DNA is a potential target for cancer treatment. However, achieving precise delivery of deoxyribozymes (DNAzymes) and combining photodynamic therapy (PDT) and DNAzyme-based gene silencing together for enhancing mitochondrial gene-photodynamic synergistic therapy remains challenging. Accordingly, herein, intelligent supramolecular nanomicelles are constructed by encapsulating a DNAzyme into a photodynamic O₂ economizer for mitochondrial NO gas-enhanced synergistic gene-photodynamic therapy. The designed nanomicelles demonstrate sensitive acid- and red-light sequence-activated behaviors. After entering the cancer cells and targeting the mitochondria, these micelles will disintegrate and release the DNAzyme and Mn (II) porphyrin in the tumor microenvironment. Mn (II) porphyrin acts as a DNAzyme cofactor to activate the DNAzyme for the cleavage reaction. Subsequently, the NO-carrying donor is decomposed under red light irradiation to generate NO that inhibits cellular respiration, facilitating the conversion of more O₂ into singlet oxygen (¹ O₂ ) in the tumor cells, thereby significantly enhancing the efficacy of PDT. In vitro and in vivo experiments reveal that the proposed system can efficiently target mitochondria and exhibits considerable antitumor effects with negligible systemic toxicity. Thus, this study provides a useful conditional platform for the precise delivery of DNAzymes and a novel strategy for activatable NO gas-enhanced mitochondrial gene-photodynamic therapy.