A Neuraminidase-Functionalized Injectable Hydrogel Depletes Sialic Acid to Disrupt the Tumor-Osteoclast Cycle and Suppress Breast Cancer Bone Metastasis.

Abstract

Breast cancer bone metastasis is characterized by aggressive osteolysis, high recurrence, and frequent secondary dissemination, driven by pathological coupling between tumor cells and osteoclasts. Effective local strategies that simultaneously suppress metastatic progression and promote bone regeneration remain limited, and the molecular vulnerabilities of the bone metastatic niche are still incompletely defined. Here, we report a neuraminidase-functionalized injectable hydrogel (HH-HP@NA) that depletes sialic acid within the bone metastatic niche to disrupt tumor-osteoclast interactions. Neuraminidase was immobilized on hydroxyapatite nanoparticles and encapsulated within a hyaluronic acid hydrogel, enabling sustained local release and enhanced enzymatic stability under acidic conditions. HH-HP@NA markedly inhibited osteoclast fusion by reducing surface sialylation, suppressed migration of MDA-MB-231 breast cancer cells, and downregulated invasion-associated molecules. In a murine model of breast cancer bone metastasis with postoperative residual tumors, local administration of HH-HP@NA achieved up to 84% tumor growth inhibition, significantly prolonged survival, and effectively prevented secondary pulmonary metastasis. Micro-CT and histological analyses further demonstrated substantial attenuation of tumor-induced osteolysis and restoration of bone microarchitecture. These results identify sialylation as a therapeutic vulnerability in the bone metastatic niche and support neuraminidase-functionalized hydrogels as a strategy for treating breast cancer-induced bone defects. STATEMENT OF SIGNIFICANCE: • Breast cancer bone metastasis functions as a metastatic reservoir that promotes systemic dissemination, yet existing bone-targeted therapies fail to block postoperative recurrence and secondary metastasis. • Aberrant sialylation emerges as a key molecular vulnerability that governs tumor-osteoclast coupling, osteolysis, and metastatic competence within the bone niche. •A neuraminidase-functionalized, microenvironment-adaptive injectable hydrogel enables sustained, localized glycan editing in the acidic bone metastatic environment. • Local desialylation simultaneously suppresses osteoclast fusion, impairs breast cancer cell migration, and disrupts the tumor-osteoclast cycle. • In vivo application results in marked inhibition of residual tumor growth, complete blockade of pulmonary dissemination, and restoration of bone microarchitecture. • Localized glycan modulation is established as a new biomaterial-based paradigm for reprogramming metastatic niches and treating tumor-induced bone defects.