Killing two birds with one stone: Siglec-15 targeting integrated bioactive glasses hydrogel for treatment of breast cancer bone metastasis

Bone metastasis is a fatal consequence of breast cancer that occurs when patients fail to respond to conventional therapies and mainly result from a vicious cycle involving dysregulated bone homeostasis and uncontrolled tumor growth. Recent research has underscored the significance of Siglec-15, a membrane protein implicated in immunosuppression and osteoclast generation. Targeting Siglec-15 may disrupt the "vicious cycle" that causes bone metastases in patients with breast cancer. Herein, we explored the efficacy of targeting Siglec-15 in conjunction with photothermal chemotherapy to impede the progression of bone metastatic during breast cancer and repair tumor-induced osteolysis. First, we formulated an injectable photothermal bioactive glass (BG)-based hydrogel for the local delivery of Siglec-15 shRNA and doxorubicin. The results demonstrated that the hydrogel could kill tumor cells directly through photothermal chemotherapy, provoke intense immune responses and improve the local immunosuppressive microenvironment, which could effectively prevent tumor metastasis and recurrence in a murine model. The combined effect of BGs and Siglec15 shRNA can normalize dysregulated bone homeostasis at the bone metastasis site and significantly reduced bone destruction. Overall, the use of Siglec-15-targeting integrated BG hydrogels may provide a promising therapeutic strategy for treating bone metastasis caused by breast cancer.