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. Here, we developed a mechanically self-reinforcing injectable hydrogel in which amino-hydroxyapatite (amHap)-encapsulating spindle-shaped tellurium (Te) nanoparticles (Te@amHap, Team) were embedded within an oxidized alginate-gelatin matrix (Te@amHap/OG Gel, Team Gel). Team Gel contains dynamic Schiff base bonds, enabling 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 TeO3 2- by osteoclast-derived H2O2. These ions can react with the thiol-containing residues of F-actin to form Te─S bonds, leading to F-actin degradation to disrupt the sealing zone and suppress bone resorption. Notably, Ca2+ from amHap interacts with alginate to form an egg-box secondary crosslinking structure, enhancing the crosslinking density beyond the original Schiff base network, thereby enhancing the mechanical strength of Team Gel and extending its retention time. Acting together, PO4 3 --mediated inhibition of osteoclast differentiation and Te-driven disruption of the mature osteoclast sealing zone suppress osteoclastogenesis and bone resorption. This sealing zone disruption strategy preserves bone quality and joint integrity, suggesting a promising osteoclast-targeted therapy for OA.