A Self-Reinforcing Hydrogel Disrupting Osteoclast Sealing Zone for Bone Erosion Alleviation
Abnormal remodeling of subchondral bone (SB), driven by osteoclast sealing zone formation and insufficient adaptation to joint mechanical stress, accelerates the progression of osteoarthritis (OA) and remains a major therapeutic challenge. In this study, we developed a mechanically self-reinforcing injectable hydrogel in which amino-hydroxyapatite (amHap)-encapsulating spindle-shaped tellurium (Te) nanoparticles were embedded within an oxidized alginate-gelatin matrix (Team Gel). Team Gel contains dynamic Schiff base bonds that enable controlled release of Team under joint mechanical forces. Within the acidic microenvironment of the osteoclast sealing zone, Team degrades and releases Te to be oxidized into TeO32- by osteoclast-derived H2O2. These ions can react with cysteine residues of F-actin to form Te-S bonds, which can lead to F-actin degradation to directly disrupt the sealing zone and suppress bone resorption. Notably, Ca2+ from amHap interacts with alginate to form an eggshell secondary crosslinking structure, which significantly increased the crosslinking density beyond the original Schiff base network, thereby enhancing the mechanical strength of Team Gel and extending its retention time. Acting in concert, PO43- -mediated inhibition of osteoclast differentiation and Te-driven disruption of mature osteoclast sealing zone synergistically suppress osteoclastogenesis and bone resorption. Such a sealing zone disruption strategy provides an effective means to preserve bone quality and maintain joint integrity, offering a promising paradigm for osteoclast-targeted therapy in OA.