Two-Photon Mediated Cancer Therapy: A Comprehensive Review on Two-Photon Photodynamic Therapy and Two-Photon-Activated Therapeutic Delivery Systems

Two-photon excitation (2PE) represents substantial advantages in biophotonics over traditional one-photon excitation (1PE), offering enhanced spatial resolution and deeper tissue penetration capabilities. Since its introduction in the 1990s, two-photon excited microscopy has spurred the rapid emergence of novel 2PE-based applications, including photodynamic therapy (PDT) and the targeted release of biologically active agents. This review first elucidates the fundamental principles of 2PE before comprehensively examining the evolution of photosensitizers (PSs) for two-photon PDT (2P-PDT), covering both nanomaterials and small molecules, categorized based on their respective characteristics. Additionally, it explores advancements in PS development for integrating 2P-PDT with other therapeutic modalities (e.g., photothermal therapy, chemotherapy, immunotherapy, gene therapy, etc.). Subsequent sections provide an overview of photoactivatable compounds with two-photon absorption properties for the controlled release of various therapeutic agents (e.g., drugs, genes, and gasotransmitters), emphasizing their potential in anticancer applications. Last, a deep discussion deciphers the prospects and challenges of 2P-mediated therapy in cancer treatment, particularly concerning their clinical translation. Two-photon excitation (2PE) has gained significant attention in biomedical applications in recent years due to its demonstrated improvements in tissue penetration and spatial selectivity. Here, it is overviewed 2P-mediated therapies, including 2P-PDT with various PSs and combined therapies, and 2P-activated release. Insights on the challenges to maximize their effectiveness in clinical contexts are also discussed. image