Self-assembled carrier-free nanomedicine suppresses tumor stemness to overcome the acquired drug-resistance of hepatocellular carcinoma

Induction of tumor stemness during traditional treatments is a pivotal factor in the development of acquired drug-resistance. The anti-angiogenic drugs represented by sorafenib (SF) over the years have always been the first-line treatment of hepatocellular carcinoma (HCC), but the drug resistance has always been a "bottleneck" in curative effect. The SF-induced upregulation of hypoxia-inducible factors (HIFs), which are the main regulators of tumor stem cell adaptation to hypoxia and nutrient deficiency, further contribute to the acquired stemness-related drug resistance in HCC. To overcome this problem, we utilized piceatannol (PCT), a food-derived traditional Chinese medicine known for its prominent HIF-1α inhibition effects, to self-assemble with Fe3+ and SF to form a carrier-free nanomedicine (FPSN) via chelation bonding. The excellent photothermal therapy (PTT) potential and the responsively disassembled properties of FPSN synergistically upregulated the oxidative stress level in HCC tissue via PTT and Fe-based ROS generation, overcoming the acquired stemness-related drug resistance that induced by HIFs and neovascularization blockade, improving the therapeutic performance of SF. The effect of FPSN was demonstrated in patient-derived xenograft (PDX) and SF-resistant HCC models, respectively, providing new insights for the treatment of acquired drug-resistant HCC.