Cartilage-Targeting Nanoparticles with a Well-Tuned Surface Charge Improve Intra-Articular Delivery of Andrographolide Derivatives for Osteoarthritis Treatment

Osteoarthritis (OA) is a degenerative joint disease characterized by the progressive destruction of cartilage, ultimately leading to joint dysfunction. Although various nanoparticle-based drug delivery systems have been designed for OA treatment, current systems still face significant challenges, particularly in achieving prolonged joint retention and efficient cartilage penetration. Herein, a cartilage-targeting nanoparticle platform composed of poly(lactic-co-glycolic acid) (PLGA), poly(allylamine) (PAA), targeting peptide, and andrographolide derivative (A100) (A100@PLGA–PAA-targeting peptide nanoparticle, i.e., A100@PLGA-P-T nanoparticle) is developed as a drug delivery system to address the above challenges. In vitro studies demonstrated that by adjustment of PAA concentrations, nanoparticles can be altered to either positively charged (A100@PLGA-P-T(+)) or neutral (A100@PLGA-P-T(n)) forms. In vitro and in vivo retention and penetration experiments showed that compared to A100@PLGA-P-T(n) nanoparticles, A100@PLGA-P-T(+) nanoparticles exhibit significantly enhanced retention time and cartilage penetration. Coculture experiments with chondrocytes revealed that A100@PLGA-P-T(+) nanoparticles significantly improved the viability of OA-like chondrocytes and increased the level of glycosaminoglycan synthesis. Furthermore, in an OA rat model, intra-articular injection of A100@PLGA-P-T(+) nanoparticles significantly reduced inflammation and promoted cartilage repair and regeneration. Collectively, the prolonged retention property, superior cartilage penetration capability, and potent anti-inflammatory and cartilage-repairing effects of the A100@PLGA-P-T(+) nanoparticle system position it as a clinically viable candidate for comprehensive OA treatment.