Co-assembly of dipeptide and hydrophobic drug in hyaluronic acid through Schiff base reaction for the treatment of osteoarthritis.

The development of multiple drugs for the synergistic osteoarthritis (OA) therapy is essential, particularly in light of the limited efficacy of existing clinical interventions. However, the poor bioavailability and systemic toxicity of hydrophobic drugs and their incompatibility with hydrophilic components largely hindered the co-delivery of multi-drugs. In this study, we present a dynamic covalent assembly strategy within a hyaluronic acid (HA) matrix to fabricate cationic dipeptide-based carrier particle (CGCP/HA). This carrier is designed to encapsulate hydrophobic nonsteroidal anti-inflammatory drug (NSAID) celecoxib and IL-1β inhibitor diacerein via a one-step co-assembly method, facilitating targeted drug delivery and combination therapy for OA. The resulting particles demonstrated exceptional stability, injectability, and biocompatibility in vitro, while mitigating the adverse effects associated with conventional oral OA medications. In a rat OA model, intra-articular administration of these co-assembled materials significantly suppressed inflammatory cytokines (TNF-α, IL-1β, and PGE2) and demonstrated enhanced cartilage repair by integrating multiple functions of hydrophilic HA, supramolecular carriers, and hydrophobic drugs. This work established a simple strategy for co-assembly of biomolecules and hydrophobic drug molecules and holds significant clinical promise for the treatment of OA.