Unveiling Volcano‐Type Trends in SOCT‐ISC Photosensitization: Energy Gap Law‐Guided Strategy for Efficient Photodynamic Therapy

ABSTRACT The development of high‐performance heavy‐atom‐free photosensitizers requires deep insight into their excited‐state dynamics. We report a series of cyanine‐based compounds functionalized at the C2 position that operate through spin–orbit charge transfer intersystem crossing (SOCT‐ISC). A pronounced “volcano‐type” relationship between photo‐induced electron transfer (PeT) efficiency and singlet oxygen quantum yield was uncovered. Femtosecond transient spectroscopy and quantum chemical calculations reveal that this trend stems from a dynamic competition between S 1 and T 2 intersystem crossing from the charge‐separated (CS) state and CS‐state charge recombination via internal conversion. The CS‐state energy serves as a key descriptor dictating this balance. By modulating the donor strength of the substituents, we optimized the CS‐state energy and identified TCy‐Pyr , a molecule near the volcano apex. TCy‐Pyr exhibits outstanding photodynamic performance, with in vitro and in vivo anticancer efficacy surpassing conventional benchmarks. It also displays aggregation‐induced targeting behavior, promoting selective tumor accumulation. This work elucidates the excited‐state dynamics in SOCT‐ISC systems and establishes a rational design strategy to overcome performance bottlenecks in photosensitizer development.