What question did this study set out to answer?

The aim is to develop a hydrogel system co-delivering diacerein and ketorolac to treat osteoarthritis more effectively.

March 26, 2026Open Access

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

Key Points

The aim is to develop a hydrogel system co-delivering diacerein and ketorolac to treat osteoarthritis more effectively.
Developed a hydrogel system incorporating diacerein solid lipid nanoparticles and ketorolac.
Optimized nanoparticles for size and concentration through central composite design.
Conducted in vitro studies for rheological properties and drug release.
Evaluated therapeutic efficacy in MIA-induced osteoarthritis rat models using behavioral and biochemical assays.
Performed molecular analyses on inflammatory and chondrogenic pathways.
DC–SLN/KT.gel reduced pain behaviors significantly in OA rats.
The treatment suppressed inflammatory markers such as NF-κB, IL-1β, and CCL2.
Collagen II preservation was noted alongside the inhibition of MMP-13.
Upregulation of SOX-9 and miR-140 was observed, indicating cartilage restoration.

Abstract

Abstract 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. Graphical Abstract

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