Tumor-Targeted Metal–Organic Framework for Improved Photodynamic Therapy and Inhibited Tumor Metastasis in Melanoma

Tumor hypoxia and elevated intracellular glutathione (GSH) levels significantly compromise the effectiveness of photodynamic therapy (PDT) in treating melanoma. In this study, we synthesized positively charged nanoparticles through a self-assembly method, incorporating photosensitizer verteporfin (VER), mitochondrial respiratory inhibitor atovaquone (ATO), and Fe³⁺. Subsequently, the nanoparticles were modified with sodium hyaluronate (HA) to obtain HA-ATO-Fe³⁺-VER nanoparticles (HAFV NPs). The fabricated HAFV NPs demonstrated excellent stability and in vitro Fenton reaction activity. HA facilitated the cellular internalization of HAFV NPs by targeting CD44 receptors, hence relieving tumor hypoxia through the disruption of the mitochondrial respiratory chain and involvement in the Fenton reaction. Simultaneously, ATO directly impeded the biosynthesis of GSH by diminishing ATP levels, while Fe³⁺ was supposed to oxidate GSH to GSSG, thereby doubly depleting GSH. The integration of these multiple mechanisms markedly enhanced the PDT efficacy of VER. Following intravenous administration, HAFV NPs preferentially accumulated in tumor tissues with minimal accumulation in the skin, demonstrating favorable biocompatibility in vivo. Furthermore, HAFV NPs effectively inhibited tumor growth and lung metastasis, which presents a promising strategy for melanoma treatment.