Unimolecular Photodynamic O₂‑Economizer To Overcome Hypoxia Resistance in Phototherapeutics

Tumor hypoxia has proven to be the major bottleneck of photodynamic therapy (PDT) to clinical transformation. Different from traditional O₂ delivery approaches, here we describe an innovative binary photodynamic O₂-economizer (PDOE) tactic to reverse hypoxia-driven resistance by designing a superoxide radical (O₂^•–) generator targeting mitochondria respiration, termed SORgenTAM. This PDOE system is able to block intracellular O₂ consumption and down-regulate HIF-1α expression, which successfully rescues cancer cells from becoming hypoxic and relieves the intrinsic hypoxia burden of tumors in vivo, thereby sparing sufficient endogenous O₂ for the PDT process. Photosensitization mechanism studies demonstrate that SORgenTAM has an ideal intersystem crossing rate and triplet excited state lifetime for generating O₂^•– through type-I photochemistry, and the generated O₂^•– can further trigger a biocascade to reduce the PDT’s demand for O₂ in an O₂-recycble manner. Furthermore, SORgenTAM also serves to activate the AMPK metabolism signaling pathway to inhibit cell repair and promote cell death. Consequently, using this two-step O₂-economical strategy, under relatively low light dose irradiation, excellent therapeutic responses toward hypoxic tumors are achieved. This study offers a conceptual while practical paradigm for overcoming the pitfalls of phototherapeutics.