Osteoarthritis (OA) is a degenerative joint disease affecting hundreds of millions worldwide. Current treatments, including oral non‑steroidal anti‑inflammatory drugs (NSAIDs), provide limited relief and carry risks of gastrointestinal and cardiovascular side effects. Intra‑articular hyaluronic acid (HA) injections offer local lubrication but lack sustained drug delivery and disease‑modifying capacity. Efficient co‑delivery of multiple hydrophobic drugs to the inflamed joint remains a major hurdle.
Now, a team led by Prof. Hengchang Zang at Shandong University reports a dynamic covalent assembly strategy that overcomes this barrier. They designed cationic dipeptide (CDP) particles crosslinked via Schiff‑base reaction with glutaraldehyde, and integrated them with HA through non‑covalent interactions. The resulting CGCP/HA carriers are spherical, auto‑fluorescent, and size‑tunable. By a one‑step co‑precipitation method, the system efficiently loads two complementary drugs: celecoxib (CLX, a COX‑2 inhibitor) and diacerein (DCR, an IL‑1β inhibitor), achieving high encapsulation efficiencies.
The carriers exhibit accelerated drug release under acidic pH, matching the inflammatory microenvironment of OA joints. In a rat model induced by papain, intra‑articular injection of the drug‑loaded particles significantly reduced serum levels of TNF‑α, IL‑1β, and PGE2. Micro‑CT and histology (H&E, Safranin O‑fast green, and immunohistochemistry) revealed restored cartilage architecture, increased proteoglycan content, and suppressed synovitis. Moreover, the formulation showed no toxicity in major organs (heart, liver, spleen, lung, kidney), whereas free drugs caused cardiac fibrosis and hepatic lymphocyte infiltration.
This work provides a simple, biocompatible, and injectable platform that synergizes the lubricating and anti‑inflammatory functions of HA with the controlled release of two hydrophobic therapeutics. The strategy not only enhances drug solubility and local bioavailability but also mitigates systemic side effects, offering a promising minimally invasive option for OA management.
The work titled “Co‑assembly of dipeptide and hydrophobic drug in hyaluronic acid through Schiff base reaction for the treatment of osteoarthritis” was published on Pharmaceutical Science Advances (published on July 4, 2026).
DOI：10.1016/j.pscia.2026.100133