Hypericum Perforatum-Derived Exosomes-Like Nanovesicles: A Novel Natural Photosensitizer for Effective Tumor Photodynamic Therapy

Background: Natural photosensitizers hold potential for photodynamic therapy (PDT) but are often limited by poor visible light absorption. Plant-derived exosome-like nanovesicles offer an innovative platform for enhancing photosensitizer performance. Methods: Hypericum perforatum-derived nanovesicles (HPDENs) were characterized using electron microscopy, dynamic light scattering, and proteomic and miRNA sequencing. High-performance liquid chromatography confirmed hypericin content. PDT efficacy was assessed in vitro and in vivo. Results: HPDENs exhibited robust photosensitizing properties, generating reactive oxygen species (ROS) through both Type I and Type II pathways upon light activation. In vitro, HPDENs showed light dose-dependent cytotoxicity against human melanoma cells, characterized by elevated ROS production and apoptosis induction. In vivo, HPDEN-mediated PDT significantly suppressed tumor growth and induced extensive tumor necrosis, with no observable toxicity to major organs. Conclusion: HPDENs represent a novel plant-derived photosensitizer with dual ROS generation pathways and significant therapeutic efficacy, providing a promising platform for enhancing photodynamic therapy.