Recent Advances in Two-Photon-Activatable Metal Complexes for Photodynamic Therapy

Photodynamic therapy (PDT) is a non-invasive modality for cancer treatment, but its broader application remains constrained by two central limitations, that is, insufficient tissue penetration of excitation light and the limited performance of available photosensitizers (PSs). Two-photon PDT (TP-PDT) offers a powerful strategy by enabling near-infrared excitation with deeper penetration, higher spatial precision, and reduced off-target photodamage. In this context, metal complexes have emerged as particularly attractive TP PSs because their coordination frameworks allow precise control over spin-orbit coupling, excited-state dynamics, redox reactivity, and reactive oxygen species generation through both Type I and Type II pathways. Recent advances show that ligand engineering, photo-decaging strategies, supramolecular design, and nanostructuring can substantially enhance two-photon absorption, charge separation, radical generation, and therapeutic efficacy, especially in hypoxic tumors. This review overviews recent progress in two-photon-activatable metal complexes for PDT, highlighting design principles and therapeutic advances across ruthenium-, iridium-, platinum-, and related metal-based complexes. Particular emphasis is given to how coordination design governs photophysical properties, biological performance, and treatment outcomes. Current challenges and future opportunities for the clinical translation of these systems are also discussed.