Dual-drug synergistic nanocomposite hydrogel with inflammation-responsive immunomodulation and BMSC recruitment for enhanced cartilage regeneration.

Articular cartilage injury often leads to progressive degeneration, necessitating advanced strategies that integrate immunomodulation, stem cell recruitment, and microenvironment regulation. Traditional hydrogels face limitations in spatiotemporal drug release and mechanical adaptability for dynamic joint environments. This study introduces an injectable, self-healing nanocomposite hydrogel engineered through dynamic boronate ester bonds between carboxymethyl chitosan and polyvinyl alcohol, synergizing macrophage-targeted curcumin nanomicelle and chondroinductive icariin. The hydrogel's reversible network enables shear-thinning injectability and reactive oxygen species (ROS)-responsive degradation, ensuring localized anti-inflammatory and pro-regenerative drug release. Curcumin-loaded mannose-functionalized micelles enhance macrophage uptake, polarizing macrophages toward an anti-inflammatory phenotype, while icariin promotes bone marrow mesenchymal stem cell (BMSC) migration and chondrogenic differentiation via Wnt/β-catenin and BMP/Smad pathway activation. In vitro studies demonstrated the hydrogel's capacity to scavenge ROS, suppress pro-inflammatory cytokines, and enhance BMSC recruitment and cartilage-specific matrix synthesis. In vivo evaluation in a rat full-thickness cartilage defect model revealed accelerated repair with organized neocartilage formation, reduced inflammation, and restored subchondral bone architecture. Histological and immunohistochemical analyses confirmed significant collagen II deposition and M2 macrophage polarization, aligning with native tissue regeneration. The hydrogel's biocompatibility and absence of systemic toxicity were validated through hematological and organ histopathology assessments. By dynamically coupling early-stage immunomodulation with sustained chondroinductive signaling, this dual-drug hydrogel disrupts the inflammation-degeneration cycle, offering a cell-free therapeutic platform for functional cartilage restoration. Its design principles provide a blueprint for intelligent biomaterials addressing complex tissue repair challenges.