Multifunctional Targeted Nanomicelles with High Cartilage Retention and pH-Responsive Drug Release for Improved Osteoarthritis Treatment

Intra-articular (IA) drug delivery for chronic osteoarthritis (OA) is associated with poor bioavailability and high frequency dosing. Although polymeric micelles have demonstrated improved cartilage penetration, dynamic joint movement and synovial clearance restrict their residence. Therefore, we engineered an actively targeted micelle that achieved prolonged retention while enabling deep cartilage penetration. PLA-PEG and DSPE-PEG were self-assembled into nanomicelles and surface-modified with a collagen-II-binding peptide. The nanomicelles showcased 100% penetration in ex vivo goat OA cartilage. A single IA injection of the targeted micelles in OA rat knee joints showed significantly higher retention for 21 days in comparison to the untargeted control, which retained for 14 days. Additionally, the nanomicelle was designed to respond to the pH change in the OA joint to attain disease-responsive drug release. Piperlongumine (PL) loaded in the micelles demonstrated ∼96% release at pH 5.6 (severe OA) and ∼81% release at pH 6.8 (mild OA) after 28 days, enabling a disease severity-dependent pH-responsive therapy. Subsequently, a single IA injection of PL-loaded micelles attenuated cartilage degradation in OA rat joints after 28 days, with a ∼50% reduction in modified Mankin scoring of OA. Overall, this system demonstrated efficient OA cartilage penetration, prolonged retention, and enabled disease-specific controlled PL release that together synergistically ameliorated OA.