A pH-responsive, surface charge-reversing biomimetic hybrid nanosystem with enhanced deep cartilage penetrability for lipid metabolic reprogramming therapy in osteoarthritis

Dysregulation of chondrocyte metabolic networks and the physical barrier imposed by the extracellular matrix (ECM) represent primary bottlenecks in precision intervention for osteoarthritis (OA). We engineered an environment-responsive, charge-adaptive biomimetic nanoplatform, IM@PP-R, in which the metabolic modulator RCGD423 was encapsulated within a polycaprolactone (PCL) core via flash nanoprecipitation (FNP), then cloaked with a hybrid shell of neutrophil membranes and ionizable lipids. In the mildly acidic OA microenvironment (pH 6.4–6.8), IM@PP-R undergoes surface charge inversion from negative to positive, converting electrostatic ECM repulsion into attraction to facilitate deep cartilage penetration. Both in vitro and in vivo, IM@PP-R treatment was associated with improved mitochondrial status and attenuated oxidative stress. This process was closely linked to a redirection of the arachidonic acid (ARA) metabolic profile: integrated transcriptomic and metabolomic analyses revealed the downregulation of pro-inflammatory enzymes (ALOX5, mPGES-1) alongside a partial recovery of the IL-1β-suppressed pro-resolving enzyme CYP2J4. These enzymatic shifts corresponded with a transition from PGE2 toward PGA2/PGJ2 accumulation, suggestive of a reprogrammed lipid mediator profile. In a rat ACLT model, IM@PP-R significantly prolonged joint residence time and attenuated osteochondral degeneration. This study presents a translatable strategy for overcoming dense tissue barriers to achieve intracellular metabolic reprogramming in OA.