Combining Type I&II Photosensitizer With Hypoxia-Activated Prodrug Enables Oxygen-Unrestricted Synergistic...

The oxygen heterogeneity within tumors restricts the therapeutic efficacy of hypoxia-activated prodrugs (HAPs) and traditional photosensitizers (PSs) when administered alone. To overcome this limitation, we present an oxygen-unrestricted synergistic therapeutic strategy to concurrently potentiate treatment efficacy in both hypoxic and normoxic tumor compartments. By introducing TEMPO, we developed an efficient PS capable of simultaneous Type I and Type II photocatalytic reactions. This PS, named DT, was co-encapsulated with the HAP TH-302 into a tumor-targeting nanoparticle system, DT@TH302, which exhibits mitochondrial localization. Upon photoactivation, DT@TH302 generates substantial amounts of singlet oxygen and superoxide anion, while disrupting the cellular NAD⁺/NADH redox equilibrium, leading to catastrophic mitochondrial dysfunction. The oxygen consumption during photodynamic therapy (PDT) further aggravates local hypoxia, thereby activating TH-302 to induce DNA cross-linking and promote tumor cell apoptosis. Meanwhile, DT-mediated PDT remains effective through a hypoxia-tolerant Type I mechanism. Moreover, the treatment triggers immunogenic cell death, demonstrating considerable potential for immunotherapy. In vivo, DT@TH302 exhibits excellent biosafety and tumor-targeting capability, resulting in significant tumor growth suppression. This work provides an oxygen-unrestricted synergistic strategy to compensate for the limitations of standalone Type II PSs or HAPs monotherapy, offering valuable insights for clinical cancer treatment.