Dual-responsive nanohydrogel system for synergistic breast cancer chemotherapy with calcium overload-mediated ion interference therapy

Breast cancer remains a leading cause of cancer-related mortality in women, while conventional chemotherapy is hindered by poor tumor selectivity, systemic toxicity, and drug resistance. Although nanocarrier-based combination therapy has shown potential, the co-delivery of multiple drugs often involves complex synthesis and unstable formulations, limiting clinical translation. In this study, camptothecin (CPT) was incorporated into CaO₂ nanoparticles and further encapsulated within a ROS-responsive PVA-TSPBA hydrogel to construct a dual-responsive nanohydrogel (CaCP@PT) for synergistic breast cancer therapy. The morphology and physicochemical properties of CaO₂, CaO₂@CPT, and CaCP@PT were analyzed by DLS, XRD, TEM, and SEM. The ROS/pH-responsive release of CPT was evaluated, followed by in vitro assessments of cytotoxicity, cellular uptake, apoptosis-related proteins, and intracellular Ca²⁺, ROS, and mitochondrial membrane potential. In vivo antitumor efficacy and biosafety were investigated in MCF-7 xenograft mice. CaO₂@CPT nanoparticles exhibited uniform spherical morphology, high encapsulation efficiency, and good stability. CaCP@PT displayed dual ROS/pH-responsive release, enhanced cytotoxicity, cellular internalization, and apoptosis induction through elevated intracellular Ca²⁺, ROS accumulation, and mitochondrial dysfunction. In MCF-7 xenograft mice, CaCP@PT achieved the most pronounced tumor suppression without body weight loss, accompanied by extensive apoptosis and inhibited proliferation. Furthermore, biosafety evaluations confirmed normal hematological and biochemical indices and no major organ damage. This in situ injectable, dual-responsive nanohydrogel enables precise, sustained drug release and integrates CPT chemotherapy with Ca²⁺-mediated ion interference, offering an effective and localized therapeutic strategy for breast cancer.