PURPOSE: The current treatment of hepatocellular carcinoma (HCC) is confronted with anoxic drug resistance and significant side effects. To address these issues, a Reactive Oxygen Species (ROS)-responsive and targeted nano drug delivery system named REG/YC-1@PTP-RGD NPs (RYP-RGD NPs) was designed for the co-delivery of Regorafenib (REG) and the hypoxia inhibitor 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1). METHODS: RYP-RGD NPs were fabricated through the self-assembly method. A series of techniques, such as transmission electron microscopy (TEM), UV-visible spectroscopy, and others, were employed to characterize their properties. In Vitro investigations encompassed drug release assays, cytotoxicity evaluations using Cell Counting Kit-8 (CCK-8) and other methods, cell uptake experiments, and Western blot analysis. In vivo, the biodistribution of RYP-RGD NPs was tracked by IVIS imaging, and their antitumor efficacy and biosafety were assessed in a HepG2 tumor-bearing mouse model with histological staining and biochemical analysis. RESULTS: RYP-RGD NPs exhibited a spherical morphology with an appropriate size and excellent dispersion. They demonstrated ROS-triggered drug release behavior. In vitro studies revealed good tumor-targeting ability, enhanced cytotoxicity against HCC cells, and the downregulation of hypoxia-inducible factor-1α (HIF-1α) by YC-1. In vivo experiments showed improved tumor targeting, significant inhibition of tumor growth, and lower toxicity compared to single drugs. CONCLUSION: The successfully developed RYP-RGD NPs offer a novel strategy for HCC treatment. They enhance drug targeting, synergistically boost the therapeutic effect, and maintain biosafety, showing great potential for clinical translation.