Deciphering the Intrinsic Chemistry of Protein‐Enhanced Type I Photodynamic Processes

Abstract Type I photodynamic therapy (PDT) shows great potential in solving the hypoxia issue of tumor treatment by producing oxygen radicals in a less O 2 ‐dependent way, attracting significant research attention. This work systematically investigates the recently discovered protein‐mediated enhancement of Type I PDT, providing critical insights into the underlying electron transfer mechanisms. These findings enable precise evaluation of protein redox potentials and establish guidelines for optimal protein screening. Through mechanism studies, cysteine is identified as the crucial redox mediator in proteins that facilitates type I photodynamic reactions. This discovery highlights cysteine‐rich proteins, such as epidermal growth factor (EGF), as ideal dual‐function agents for enhancing PDT. By conjugating EGF with an organic photosensitizer, a 3.3‐fold increase in superoxide anion (O 2 •− ) production and a 2‐fold improvement in tumor accumulation are demonstrated. Both in vitro and in vivo studies consistently show superior therapeutic outcomes, confirming the synergy between enhanced photodynamic efficiency and targeted delivery upon the EGF conjugation. These findings provide important insights for the rational selection of protein modifiers in the design of photosensitizers, establishing a new paradigm for the development of high‐efficiency PDT systems.