In-Cell Photoactivated Porphyrin Demetalation for Reductive Photodynamic Therapy under Hypoxia

Photocontrolled metal ion release systems for hypoxic tumor therapy are rare. Metalloporphyrins can realize photoactivated hydride (H^-) therapy under hypoxia, but studies combining H^- therapy with metal ion release have not been reported. Herein, we reported that zinc-coordinated porphyrin (ZnPor) can undergo photochemical Zn²⁺ release, accompanied by photoconversion of ZnPor into phlorin (Phl) as a H^- donor, providing a pathway for the conversion between metalloporphyrins and porphyrins based on the instability of phlorins. Further, morpholine-modified metalloporphyrin (^lysoZnPor) is photoactivatable in situ to undergo demetalation for lysosome-targeted H^- therapy. Driven by light and endogenous 1,4-dihydronicotinamide adenine dinucleotide (NADH), ^lysoZnPor releases Zn²⁺ and generates ^lysoPhl. The photoredox cycle between phlorin and porphyrin harnesses NADH as a hydride donor, and ubiquinone as an electron acceptor induces lysosomal dysfunction and consequently cell death, achieving photoactivated H^- therapy on hypoxic tumor cells. This study highlights the potential of photocontrolled porphyrin demetalation and reductive photodynamic therapy.