The Tumor Microenvironment (TME) is characterized by low pH, hypoxia, and overexpression of glutathione (GSH). Owing to the complexity of tumor pathogenesis and the heterogeneity of the TME, achieving satisfactory efficacy with a single treatment method is difficult, which significantly impedes tumor treatment. In this study, composite nanoparticles of calcium-copper/alginate-hyaluronic acid (CaO2-CuO2@SA/HA NC) with pH and GSH responsiveness were prepared for the first time through a one-step synthesis using hyaluronic acid (HA) as a targeting ligand. Nanoparticles loaded with H2O2 can enhance the ChemoDynamic Therapy (CDT) effects. Simultaneously, Cu2+ can generate oxygen in the TME and alleviate hypoxia in tumor tissue. Cu2+ and H2O2 undergo the Fenton reaction to produce cytotoxic hydroxyl radicals and Ca2+ ions, which enhance the localization and clearance of nanoparticles in tumor cells. Additionally, HA and sodium alginate (SA) were utilized to improve the targeting and biocompatibility of the nanoparticles. FTIR, XRD, DLS, SEM, TEM, and other analytical methods were used to investigate their physical and chemical properties. The results indicate that the CaO2-CuO2@SA/HA NC prepared using a one-step method had a particle size of 220 nm, a narrow particle size distribution, and a uniform morphology. The hydrogen peroxide self-supplied nanodrug delivery system exhibited excellent pH-responsive release performance and glutathione-responsive •OH release ability while also reducing the level of reactive oxide species (ROS) quenching. In vitro cell experiments, no obvious side effects on normal tissues were observed; however, the inhibition rate of malignant tumors HepG2 and DU145 exceeded 50%. The preparation of CaO2-CuO2@SA/HA NC nanoparticles, which can achieve both chemokinetic therapy and ion interference therapy, has demonstrated significant potential for clinical applications in cancer therapy.
