Integrated hydrogel system targeting AMPK/PPARγ signaling in osteoarthritis immunometabolic regulation.

This study introduces CA@PDX HMs, an injectable sustained-release hydrogel system for osteoarthritis (OA) therapy designed to regulate the immunometabolic microenvironment via the AMPK/PPARγ signaling pathway. The hydrogel consists of Protectin DX (PDX)-loaded microspheres embedded within an OHA/CMC-ADH matrix and is fabricated using a microfluidic strategy to achieve high encapsulation efficiency and controlled drug release. PDX demonstrated anti-inflammatory effects by suppressing pro-inflammatory cytokines and promoting M2 macrophage polarization. In vitro, CA@PDX HMs reduced chondrocyte apoptosis and matrix degradation, restoring key cartilage components. In an ACLT-induced OA rat model, intra-articular administration of CA@PDX HMs markedly improved cartilage integrity, reduced OARSI scores, and enhanced IL-10 expression. Transcriptomic analysis revealed significant enrichment of the AMPK/PPARγ pathway, indicating coordinated regulation of metabolic and inflammatory processes. Mechanistic validation further confirmed activation of p-AMPK and PPARγ signaling, accompanied by suppression of inflammatory mediators and remodeling of the local immune microenvironment. These findings highlight the hydrogel's anti-inflammatory, anti-apoptotic, and matrix-protective effects, showcasing its potential as a promising localized treatment for OA with excellent biocompatibility and retention characteristics.