Intra-articular dual-targeted hydrogel co-delivering diacerein nanoparticles and ketorolac for modulating neuroimmune interplay and cartilage degeneration in osteoarthritis

Osteoarthritis (OA) is a multifactorial joint disease characterized by cartilage degradation, chronic inflammation, and persistent pain, yet current treatments provide only symptomatic relief without altering disease progression. This study aimed to develop and evaluate an intra-articular co-delivery system of diacerein (DC) using solid lipid nanoparticles (SLN) and ketorolac (KT) incorporated into a hydrogel matrix (DC-SLN gel) for synergistic cartilage protection and pain relief. SLN were optimized for particle size and polydispersity index by central composite design. In addition to zeta potential, entrapment efficiency, DSC, TEM, and stability assessment. The hydrogel composed of xanthan gum and sodium hyaluronate was characterized for rheological and in vitro release studies. In vitro release studies confirmed sustained DC release for prolonged chondroprotection and rapid KT release for acute analgesia. Therapeutic efficacy was evaluated in MIA-induced OA rats through behavioral assays, histological scoring, biochemical markers, and molecular analyses of inflammatory and chondrogenic pathways. DC-SLN/KT.gel demonstrated superior outcomes compared to free drugs or single-drug formulations. It significantly reduced pain behaviors, suppressed NF-κB, IL-1β, CCL2, and Substance P, and lowered CD68⁺ macrophage infiltration. Concurrently, it preserved collagen II, inhibited MMP-13, and upregulated SOX-9 and miR-140, restoring cartilage homeostasis. In conclusion, embedding SLN within an injectable hydrogel enabled targeted, site-specific, and sustained intra-articular drug delivery, reducing systemic exposure while enhancing efficacy. These results demonstrate the DC-SLN gel as a promising translational platform that unites targeted pain management with disease-modifying potential for advanced OA therapy.