Near infrared-assisted Fenton reaction for tumor-specific and mitochondrial DNA-targeted photochemotherapy

The strong dependence on oxygen level, low ultraviolet/visible (UV/vis) light penetration depth and the extremely short lifetime of reactive oxygen species (ROS) are the major challenges of photodynamic therapy (PDT) for tumors. Fenton reaction can produce abundant ROS such as reactive hydroxyl radicals (^[rad]OH) with significantly higher oxidation performance than singlet oxygen (¹O₂), which, however, has been rarely used in biomedical fields due to strict reaction conditions (favorably in pH range of 3–4, mostly under UV/vis light catalysis). Herein we propose and demonstrate a photochemotherapy (PCT) strategy of cancer therapy using near-infrared (NIR)-assisted tumor-specific Fenton reactions. NIR light-upconverted UV/vis light by upconversion nanoparticles (UCNPs) catalyze the intra-mitochondrial Fenton reaction between the delivered Fe²⁺ and H₂O₂ species over-expressed in cancer cell's mitochondria to in-situ kill the cancer cells. The intra-mitochondrial ROS generation of enabled by directly targeting the mitochondrial DNA (mtDNA) helix minimized the distance between the ROS and mtDNA molecules, thus the present PCT strategy showed much enhanced and tumor-specific therapeutic efficacy, as demonstrated by the intratumoral-accelerated [rad]OH burst and elevated cytotoxicity. Following the direct intratumoral injection, the PCT revealed marked tumor regression effect in vivo. This constructed PCT-agent is the first paradigm of NIR-upconversion catalyzed intra-mitochondrial Fenton reaction in response to tumoral microenvironment, establishing a novel photochemotherapy strategy for efficient cancer therapy.