Self-oxygenating PCN-224(Mn) co-delivers sorafenib and plumbagin to boost chemo-photodynamic therapy in hepatocellular carcinoma

Tumor hypoxia is a major barrier to oxygen-dependent photodynamic therapy (PDT), markedly limiting its therapeutic efficacy in hepatocellular carcinoma (HCC). Herein, a self‑oxygenating and redox-amplifying metal-organic framework (MOF) nanoplatform is constructed by co-loading sorafenib (Sor) and plumbagin (PLB) into a surface galactose functionalized Mn-porphyrinic PCN-224(Mn) (PM) framework to afford SorPLB@Gal-PM for asialoglycoprotein receptor (ASGPR)-mediated HCC targeting. The Mn-porphyrin centers endow SorPLB@Gal-PM with catalase-like activity, enabling in situ decomposition of endogenous H 2 O 2 to generate O 2 and thereby sustaining 1 O 2 -based PDT under irradiation. Meanwhile, Sor/PLB co-delivery, together with PLB-mediated GPX4 suppression, promotes oxidative stress amplification. In hypoxic liver cancer stem cell-like C5WN1 cells, SorPLB@Gal-PM elicits markedly enhanced intracellular ROS upon irradiation, showing approximately 3.4-fold and 2.9-fold higher DCFH-DA signals than SorPLB@Gal-PCN-224 and PM, respectively, accompanied by downregulation of hypoxia-inducible factor-1α (HIF-1α) and glutathione peroxidase 4 (GPX4). In a C5WN1 tumor-bearing nude mouse model, SorPLB@Gal-PM combined with irradiation achieves the most potent tumor suppression with a tumor inhibition rate of 83.70% ± 4.12%. Collectively, SorPLB@Gal-PM provides a hypoxia-adaptive nanoplatform integrating Mn-assisted self‑oxygenation and redox-amplified chemo-PDT for effective HCC therapy.