pH-responsive hydrogel with gambogic acid and calcium nanowires for promoting mitochondrial apoptosis in osteosarcoma.

Calcium (Ca) overload therapy gained significant attention in oncology. However, its therapeutic efficacy remained limited due to insufficient Ca accumulation at the tumor site and suboptimal intracellular Ca influx. In this study, gambogic acid (GA), a natural phenolic compound known to promote Ca influx, was encapsulated within an enzyme-triggered, pH-responsive hydrogel (GM@Lip@CHP-Gel) containing Ca hydrogen phosphate nanowires (CHP) to achieve a synergistic approach for bone tumor therapy. GM@Lip@CHP-Gel selectively responded to the slightly acidic tumor microenvironment, triggering degradation of its 3D network structure and sustaining the release of GA and Ca into tumor cells. GA subsequently stimulated Ca influx in tumor cells, effectively disrupting Ca homeostasis. CHP nanowires served as a continuous Ca source, enhancing GA-mediated Ca overload and promoting mitochondrial apoptosis in tumor cells. The combined strategy resulted in an in vivo tumor suppression rate of 79 % and a lung metastasis inhibition rate of 89.4 %, with a protective effect on bone tissue. The naturally derived, Ca-mediated treatment demonstrated physiochemical stability in physiological environments and minimized side effects on healthy organs, positioning it as a promising approach for clinical bone cancer therapy.