An injectable dihydroartemisinin nanocomposite hydrogel for dual-targeting PANoptosis and inflammation to treat osteoarthritis.

PANoptosis, a distinct type of inflammation-associated programmed cell death that integrates features of apoptosis, necroptosis and pyroptosis, is closely related to the pathogenesis and progression of articular cartilage degeneration in osteoarthritis (OA). Meanwhile, excessive reactive oxygen species (ROS), pro-inflammatory pathways, and inflammatory cytokines in the OA microenvironment mutually reinforce one another, exacerbating synovial inflammation. To simultaneously target these interconnected pathological drivers, we developed an injectable nanocomposite thermosensitive hydrogel (DHA-PRO@NMs@TSH). This hierarchical system was constructed by integrating a ROS-responsive dihydroartemisinin prodrug (DHA-PRO) into Soluplus/TPGS-based nanomicelles (NMs), which were subsequently embedded within a Poloxamer-based thermosensitive hydrogel (TSH). This hierarchical and smart drug delivery system enables stable dihydroartemisinin (DHA) delivery and demonstrates a graded, ROS-triggered release profile, achieving sustained DHA retention in OA joints. The formulated system demonstrated excellent injectability, thermosensitivity, and physicomechanical stability, achieving sustained drug retention in rat joints for over 7 days, as confirmed by in vivo imaging. In vitro studies demonstrated that DHA-PRO@NMs significantly suppressed PANoptosis in chondrocytes by downregulating key markers (e.g., Bax/Bcl-2, RIPK3/p-RIPK3, NLRP3/Caspase-1/GSDMD) and inhibited inflammation by blocking the NF-κB pathway and subsequent cytokine production (e.g., TNF-α, IL-1β). In a rat OA model, treatment with DHA-PRO@NMs@TSH robustly attenuated disease progression, as evidenced by near-complete restoration of gait function, marked inhibition of cartilage degradation, a remarkable nearly 90% reduction in the Mankin score, and a comprehensive suppression of PANoptosis and inflammation pathological markers. This work not only presents a promising translational strategy for OA but also pioneers a therapeutic paradigm of leveraging advanced drug delivery system to dual-targeting PANoptosis and inflammation.