Abstract

Bone metastasis is a significant challenge in the treatment of advanced breast cancer, with current treatments mainly providing symptom relief without addressing the osteolytic cycle driven by tumor cells and osteoclasts, which leads to continuous bone destruction and tumor progression. Pamidronate (APD), a nitrogen-containing bisphosphonate, has shown potential in managing osteolytic lesions by inhibiting osteoclast activity. However, its clinical application is hindered by rapid systemic clearance and off-target effects. Herein, we developed a multifunctional injectable hydrogel (CHA) by covalently conjugating APD to enhance localized delivery, reduce toxicity, and target both tumor progression and bone degradation to disrupt osteolytic cycle. The CHA hydrogel induces membrane calcification in tumor cells, forming a mineralized layer that impairs nutrient exchange and suppresses tumor growth. Concurrently, CHA modulates the bone microenvironment by downregulating PTHrP expression, inhibiting osteoclastogenesis, and promoting osteogenesis through the upregulation of OPG and RUNX2. Both in vitro and in vivo experiments demonstrated that CHA significantly inhibited tumor growth, prevented bone loss, and facilitated bone regeneration. Moreover, CHA exhibited excellent biocompatibility with no observed systemic toxicity. These results underscore the promise of CHA as a clinically translatable therapeutic strategy for the treatment of osteolytic bone metastases.