Calcium (Ca2+) overload therapy gained significant attention in oncology. However, its therapeutic efficacy remained limited due to insufficient Ca2+ accumulation at the tumor site and suboptimal intracellular Ca2+ influx. In this study, gambogic acid (GA), a natural phenolic compound known to promote Ca2+ influx, was encapsulated within an enzyme-triggered, pH-responsive hydrogel (GM@Lip@CHP-Gel) containing Ca2+ 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 Ca2+ into tumor cells. GA subsequently stimulated Ca2+ influx in tumor cells, effectively disrupting Ca2+ homeostasis. CHP nanowires served as a continuous Ca2+ source, enhancing GA-mediated Ca2+ 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, Ca2+-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.Copyright © 2024. Published by Elsevier B.V.