Polyethylene glycol-maleimide amphiphilic carboxymethyl-hexanoyl chitosan enables cadherin-11-targeted hyaluronan synthase 2 delivery and hyaluronan biosynthesis in osteoarthritis.

Osteoarthritis (OA) is a multifactorial joint disease characterized by progressive cartilage degeneration and chronic inflammation of the synovial membrane. A critical hallmark of OA is the depletion of high-molecular-weight hyaluronan (HA), which impairs lubrication and perpetuates a catabolic microenvironment. To restore endogenous HA biosynthesis, we engineered a cadherin-11 (CDH11)-targeted, pH-responsive nanocarrier (CMN-CDH11) based on amphiphilic carboxymethyl-hexanoyl chitosan-poly(ethylene glycol)-maleimide for the intracellular delivery of hyaluronan synthase 2 (HAS2). These nanocarriers (∼350 nm) leveraged a pH-triggered charge-reversal mechanism, transitioning from -10.88 mV at pH 7.0 to a positive potential of +34.40 mV at pH 4.5. Confocal imaging confirmed that this strategy facilitated endosomal escape, enabling cytosolic delivery of enzymatically active HAS2 for subsequent HA biosynthesis. In vitro results in fibroblast-like synoviocytes demonstrated that CDH11-mediated targeting enhanced cellular association by 2.5-fold, leading to a significant upregulation of HAS2 expression and secretion of bioactive HA with a weight-average molecular weight of 2.05 MDa. In a rabbit ACLT model with three animals per group, HAS2@CMN-CDH11 treatment promoted superior matrix regeneration and sulfated glycosaminoglycan deposition compared with conventional HA injections. We further demonstrated that the HAS2@CMN-CDH11 platform transitioned OA therapy from exogenous HA supplementation to cell-mediated HA production within a 6-week observation period, highlighting its potential as a therapeutic strategy for osteoarthritis.