Hydrogel-guided p-LOX nanodrug delivery modulates metabolic microenvironment for cartilage repair in osteoarthritis.

Osteoarthritis (OA) is a common degenerative disorder characterized by joint inflammation and progressive loss of cartilage. Anti-OA therapies are still lacking. The hallmark of OA pathoetiology is an imbalance in metabolic activities that causes persistent inflammation and an intrinsic loss of regenerative capacity. In the present study, we discovered that lysyl oxidases (LOXs) were downregulated in clinical samples of patients with OA. LOX supplementation remodeled the metabolic microenvironment via an anti-inflammatory effect. We constructed a positively charged LOX-based (p-LOX) nanodrug delivery system guided by a hydrogel (HG), which consisted of photo-crosslinked hyaluronic acid and dopamine. The HG-p-LOX system delivered sustained release of the p-LOX nanodrug for up to 20 days following a one-time intra-articular administration, which effectively repaired cartilage defects and inhibited the pathoetiology of OA. Mechanistically, we discovered that HG-p-LOX delivery altered the OA microenvironment by targeting glycolysis-mediated lactate production in chondrocytes. p-LOX was observed to exert a hitherto unrecognized role in modulating histone lactylation, which is essential for the transcription of target genes linked to inflammatory conditions. We also used SRY-Box Transcription Factor 9-Cre recombinase mutated estrogen receptor 2/lactate dehydrogenase Afloxed/floxed transgenic mice to validate the critical role of lactate in LOX-mediated inflammation. Thus, the HG-p-LOX nanodrug delivery system may represent a novel drug target and a potential clinical treatment for OA repair.