Hypoxia-relieving and glycolysis-disrupting polydopamine nanomedicine for synergistic chemo-photothermal therapy of hepatocellular carcinoma

Hypoxia is a hallmark of solid tumors that compromises therapeutic efficacy in hepatocellular carcinoma (HCC). Here, a multifunctional polydopamine (PDA)-based nanomedicine co-loading shikonin (SK) and catalase (CAT) and functionalized with galactose (Gal) is developed and termed SC@PDA-Gal. SC@PDA-Gal delivers SK to inhibit pyruvate kinase M2 (PKM2) and disrupt glycolytic output, while the co-delivered CAT decomposes endogenous H₂O₂ to generate O₂ in situ, thereby downregulating HIF-1α and alleviating hypoxia. Under hypoxic conditions, SC@PDA-Gal reduces lactate production by 51% (vs. control) and depletes intracellular adenosine triphosphate (ATP) by 89% (vs. control) in HCC cells, indicating effective glycolysis suppression. Moreover, PDA enables efficient photothermal conversion under near-infrared (NIR) irradiation, providing localized hyperthermia and accelerating drug release. In vivo, SC@PDA-Gal achieves a tumor inhibition rate of 93.44 ± 2.86% in subcutaneous C5WN1-bearing mice with favorable biosafety. Collectively, SC@PDA-Gal represents a targeted, hypoxia-adaptive chemo-photothermal nanomedicine for precision HCC therapy.