Intermolecular Electron Transfer: Toward a General Photochemical Engine for Type I Photodynamic Therapy

Hypoxia is an intrinsic characteristic within tumors or infected tissues, which poses a significant barrier to effective photodynamic therapy (PDT). Type I PDT is a promising complement or alternative to conventional Type II PDT owing to its reduced or absent reliance on molecular oxygen. Type I photosensitizers (PSs) are essential to Type I PDT, which undergoes photoinduced electron transfer with biological substrates to produce cytotoxic radical species (O₂⁻•, •OH) for the targeted destruction of pathological tissues. However, the limited mechanistic understanding of photoinduced electron transfer makes the rational design of Type I PSs a great challenge. Encouragingly, compelling evidence reveals that intermolecular electron transfer (InterET) is not an obscure mechanism, but rather the predominant photochemical engine driving Type I PDT. This Perspective reviews the evolution and challenges of InterET in Type I PDT, with a particular focus on semiempirical design principles for InterET-based Type I PSs. Finally, it is concluded with an outlook on future opportunities and remaining challenges in the development of next-generation Type I PSs.