Two-Photon-Activated Heavy-Atom Free AIEgen for Highly Efficient Type I Photodynamic Therapy

The therapeutic efficacy of photosensitizers in photodynamic therapy (PDT) largely depends on the reactive oxygen species production, types, and tissue penetration depth. Particularly in malignant tumors, hypoxia is widely recognized as a major obstacle for PDT. Herein, a two-photon-excitable heavy-atom free photosensitizer PNF is designed. PNF can be used as a type‑I photosensitizer to overcome the limitations of PDT in treating hypoxic tumors. The photosensitizer PNF exhibits distinct aggregation-induced emission characteristics and can generate O₂^•− and OH^• through type I photochemical processes upon 808 nm laser irradiation. The two-photon-activated PDT induced by PNF disrupts cellular redox homeostasis, and increases levels of lipid peroxidation, leading to apoptosis, as well as ferroptosis. In vitro and in vivo experiments demonstrate the effectiveness of this synergistic treatment strategy in inhibiting the growth of hypoxic cancer cells and tumors.