Natural Product-Based Upconversion-Downshifting Photosensitizers in Photodynamic Therapy

Natural product-based upconversion photosensitizers (PSs) have emerged as innovative agents in photodynamic therapy (PDT). Lanthanide ions such as Yb³⁺, Er³⁺, Nd³⁺, Gd³⁺, and Tm³⁺ have unique photophysical properties and biocompatibility, exhibiting sharp 4f-4f transitions and long-lived excited states involving the dual luminescence processes, upconversion and downshifting. Natural product photosensitizers (PSs), including coumarin, riboflavin, curcumin, chlorophyll derivatives, and hypocrellin, offer superior safety profiles compared with synthetic PSs. Recent advances in upconversion nanoparticles (UCNPs) and upconversion-downshifting nanoparticles (UDNPs) for the generation of ROS in PDT have been evaluated. This narrative review surveyed the literature published between 1995 and 2026 across multiple electronic databases, including WanFang Data, PubMed, ScienceDirect, Scopus, Web of Science, Springer Link, SciFinder, and the China National Knowledge Infrastructure (CNKI), without language restrictions. The search focused on studies related to photodynamic therapy, lanthanide photophysics, and natural product photosensitizers such as coumarin, riboflavin, curcumin, chlorophyll derivatives, and hypocrellin, as well as nanoplatforms involving upconversion (UCNPs) and upconversion-downshifting nanoparticles (UDNPs). Relevant publications were identified and synthesized to integrate advances in lanthanide photophysics, natural product PSs, and nanoplatform design into a conceptual framework. Natural product-based upconversion PSs for PDT have the advantages of low dark toxicity, biocompatibility, and multimodal actions. Lanthanide-enhanced systems overcome these issues, including shallow tissue penetration, photobleaching, and relatively low singlet oxygen quantum yields. Thus, natural product-based upconversion PSs in PDT are an innovative strategy, but bridging preclinical promise with clinical translation remains a critical future challenge.