Sono‐Controllable Janus Hydrogel Platform for Sequential Tumor Eradication and Bone Regeneration in Metastatic Breast Cancer

Sequential tumor eradication and bone regeneration remain a significant challenge for patients with breast cancer bone metastases. This study develops a novel Janus hydrogel platform, which can achieve tumor elimination and bone repair under the action of different ultrasound frequencies. Moreover, the sustained‐release oxygen can improve the hypoxic microenvironment for synergistic enhancement of efficacy. Abstract Bone metastases occur in 60%–75% of patients with metastatic breast cancer, reducing survival rates and compromising quality of life. Innovative treatments are urgently needed to sequentially eradicate tumor cells and promote bone regeneration. In this study, a novel Janus hydrogel platform (GA@CaMP) is developed for encapsulating the sonosensitive composite nanomaterial MHP, which enables gene expression regulation, along with oxygen‐releasing CaO2 NPs. The platform's therapeutic efficacy is achieved through two distinct mechanisms: high‐concentration ROS, activated under specific ultrasonic conditions, synergizes with the upregulation of ZBP1 expression to co‐activate the necroptotic pathway, inducing tumor cell death and effectively eliminating residual cancer cells. Subsequently, low‐concentration ROS stimulates osteogenic gene expression, promoting bone regeneration in affected areas. The incorporation of CaO2 NPs further enhances therapeutic outcomes through continuous oxygen release, which improves the local hypoxic microenvironment and consequently promotes more effective tumor eradication and bone regeneration. This multifunctional Janus hydrogel system demonstrates remarkable efficacy in tumor clearance and bone defect repair, representing a significant advancement in the comprehensive treatment of bone metastatic breast cancer. The platform's dual functionality and therapeutic precision position it as a promising strategy for holistic breast cancer management, with substantial potential for clinical translation and application in cancer therapy. Sequential tumor eradication and bone regeneration remain a significant challenge for patients with breast cancer bone metastases. This study develops a novel Janus hydrogel platform, which can achieve tumor elimination and bone repair under the action of different ultrasound frequencies. Moreover, the sustained-release oxygen can improve the hypoxic microenvironment for synergistic enhancement of efficacy. Abstract Bone metastases occur in 60%–75% of patients with metastatic breast cancer, reducing survival rates and compromising quality of life. Innovative treatments are urgently needed to sequentially eradicate tumor cells and promote bone regeneration. In this study, a novel Janus hydrogel platform (GA@CaMP) is developed for encapsulating the sonosensitive composite nanomaterial MHP, which enables gene expression regulation, along with oxygen-releasing CaO 2 NPs. The platform's therapeutic efficacy is achieved through two distinct mechanisms: high-concentration ROS, activated under specific ultrasonic conditions, synergizes with the upregulation of ZBP1 expression to co-activate the necroptotic pathway, inducing tumor cell death and effectively eliminating residual cancer cells. Subsequently, low-concentration ROS stimulates osteogenic gene expression, promoting bone regeneration in affected areas. The incorporation of CaO 2 NPs further enhances therapeutic outcomes through continuous oxygen release, which improves the local hypoxic microenvironment and consequently promotes more effective tumor eradication and bone regeneration. This multifunctional Janus hydrogel system demonstrates remarkable efficacy in tumor clearance and bone defect repair, representing a significant advancement in the comprehensive treatment of bone metastatic breast cancer. The platform's dual functionality and therapeutic precision position it as a promising strategy for holistic breast cancer management, with substantial potential for clinical translation and application in cancer therapy. Advanced Science, Volume 12, Issue 43, November 20, 2025.