Combining Type I&II Photosensitizer With Hypoxia‐Activated Prodrug Enables Oxygen‐Unrestricted Synergistic Photocatalytic Therapy

ABSTRACT 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.