Cartilage deterioration is the hallmark of osteoarthritis (OA). Rapid clearance of intra-articularly injected drugs and inherent cartilage barrier properties represent enormous challenges facing the effective local OA therapy. Rhein (RH), a dihydroxy-anthraquinone acid molecule, possess a potential chondroprotective effect. However, RH suffers from poor oral bioavailability besides its gastrointestinal side effects. Herein, for the first time, we exploited cationic carriers to target anionic cartilage matrix to create a RH-reservoir within the cartilage matrix, improving RH therapeutic efficacy with reduced side effects. Firstly, we improved RH lipophilic characteristics employing hydrophobic ion pairing (HIP) to be efficiently loaded within lipid nanoparticles with slow-release properties. RH-HIP integrated solid lipid nanoparticles (RH-SLNs) rapidly penetrated through cartilage tissue and lasted for 3 weeks into healthy and arthritic rat joints. Furthermore, RH-SLNs significantly inhibited inflammatory response, oxidative stress and cartilage deterioration in MIA-arthritic rats. In conclusion, intra-articular cationic RH-SLNs represented a meaningful step towards OA therapy.
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