Organic photosensitizers: from molecular design to phototheranostics

Abstract

Photodynamic therapy (PDT) has emerged as a highly promising approach for tumor treatment, owing to its remarkable spatiotemporal precision and non-invasive characteristics. Nevertheless, the clinical translation of conventional organic photosensitizers remains constrained by inherent limitations, including a low photosensitization effect, limited reactive oxygen species (ROS) production in a hypoxic tumor microenvironment (TME), restricted tissue penetration depth, and inefficient tumor-targeting. To address these challenges, this review examines molecular engineering strategies through rational structure design, focusing on five critical aspects: (i) to promote the intersystem crossing (ISC) process by introducing heavy atoms, designing photosensitizers with a twisted conformation structure or polymerization for amplified ROS generation; (ii) to conquer tumor hypoxia via construction of type I photosensitizers, fractional photosensitizers and other radical-generating photosensitizers; (iii) to excite with near-infrared light via constructing a D–A structure, fabricating J-aggregates, or utilizing two-photon excitation to improve the penetration depth; (iv) to target tumor tissues through conjugating photosensitizers with tumor-specific ligands or gene-encoded fragments to achieve tumor-targeted therapy; and (v) to reduce the off-target effect via designing TME-activatable photosensitizers. Additionally, this review highlights emerging applications in precision oncotherapy, antimicrobial therapy, and afterglow imaging diagnostics. Moreover, the perspectives and challenges of the molecular design and phototheranostics of organic photosensitizers are discussed. This review aims to bridge fundamental research with clinical translation challenges, providing strategic insights for advancing next-generation organic photosensitizers.