Trifunctional Sialylation‐Based SF‐ZIF@NA Hydrogel for Selective Osteoclast Inhibition and Enhanced Bone‐Vessel Regeneration in Osteoporotic Bone Defects

Abstract Osteoporotic bone defects are challenging to repair due to imbalances in bone resorption and formation, coupled with insufficient vascularization. To address these issues, it develops a trifunctional hydrogel (SF‐ZIF@NA) designed to selectively inhibit osteoclast activity and enhance vascularized bone regeneration. By enzymatically removing sialic acid, SF‐ZIF@NA prevents precursor osteoclasts (pOCs) from fusing into bone‐resorbing mature osteoclasts (mOCs), thereby preserving pOCs and their anabolic functions. Additionally, the hydrogel releases Zinc ion (Zn²⁺) in response to acidic conditions, promoting osteogenesis and angiogenesis. In vitro results confirmed that SF‐ZIF@NA impedes osteoclast fusion, enhances platelet‐derived growth factor‐BB (PDGF‐BB secretion from pOCs, and activates the FAK (focal adhesion kinase) signaling pathway to stimulate vascularized bone formation. In osteoporotic bone defect models, SF‐ZIF@NA accelerated bone repair with increased bone density and vascularization. These findings demonstrate that SF‐ZIF@NA offers a targeted and multifunctional strategy for osteoporotic bone regeneration by concurrently modulating osteoclast activity and promoting angiogenesis.