A thermally triggered, in situ-forming tropoelastin hydrogel enables programmed control of stem cell-driven cartilage regeneration in osteoarthritis.

Osteoarthritis (OA) is characterized by irreversible cartilage degeneration, and current therapies offer only symptomatic relief without true regeneration. Endogenous mesenchymal stem cells (MSCs)-based repair strategies hold promise but are hindered by inefficient recruitment, poor retention on damaged cartilage, anoikis, and non-programmed differentiation. Here, we report a multifunctional in situ-forming tropoelastin-alginate hydrogel engineered for programmed control of endogenous MSCs-driven cartilage regeneration. The system integrates three synergistic modules: a stem cell-recruiting peptide (SKP) to attract diverse endogenous MSCs, cartilage-targeting thermosensitive particles (CaCl₂@1-TDC/WYR) enabling precise anchoring to damaged cartilage and ion-triggered rapid gelation, and tropoelastin (TE) to enhance MSCs proliferation and chondrogenic differentiation. Upon intra-articular injection, the hydrogel undergoes targeted "Recruit-Anchor-Differentiate" programming: SKP/TE mediate efficient MSCs homing, thermosensitive particles ensure stable cartilage surface localization and retention of recruited cells, while the TE-rich matrix supports proliferation and lineage-specific differentiation. In vitro, the hydrogel demonstrated robust MSCs recruitment, viability preservation under anoikis-inducing conditions, and enhanced chondrogenic marker expression. In an OA rat model, it achieved superior cartilage repair, reduced osteoarthritic degeneration, and restored biomechanical properties compared with controls. This spatiotemporally programmed hydrogel overcomes major limitations of endogenous MSC therapy, offering a promising platform for minimally invasive, cell-free cartilage regeneration in OA.