Heterodimeric Photosensitizer as Radical Generators to Promoting Type I Photodynamic Conversion for Hypoxic Tumor Therapy

Abstract Photodynamic therapy (PDT) using traditional type II photosensitizers (PSs) has been limited in hypoxic tumors due to excessive oxygen consumption. The conversion from type II into a less oxygen‐dependent type I PDT pathway has shown the potential to combat hypoxic tumors. Herein, the design of a heterodimeric PS, NBSSe , by conjugating a widely used type I PS NBS and a type II PS NBSe via molecular dimerization, achieving the aggregation‐regulated efficient type I photodynamic conversion for the first time is reported. Electrochemistry characterizations and theoretical calculations elucidate that NBSSe tends to form a S +· /Se −· radical pair via intramolecular electron transfer in the co‐excited NBSSe * aggregate, realizing 7.25‐fold O 2 −· generation compared to NBS and 80% suppression of 1 O 2 generation compared to NBSe . The enhanced O 2 −· generation of NBSSe enables excellent anti‐hypoxia PDT efficiency and inhibition of pulmonary metastasis. Additionally, the incorporation of electron‐rich bovine serum albumin accelerates the recycling of cationic PS radical NBSSe +· , further boosting photostability and O 2 −· generation. The resultant BSA@NBSSe nanoparticles demonstrate successful tumor‐targeting PDT capability. This work provides an appealing avenue to convert ROS generation from the type II pathway to the type I pathway for efficient cancer phototherapy in hypoxia.