Hyaluronic-Acid-Nanomedicine Hydrogel for Enhanced Treatment of Rheumatoid Arthritis by Mediating Macrophage-Synovial Fibroblast Cross-Talk.

The occurrence of rheumatoid arthritis (RA) is highly correlated with progressive and irreversible damage of articular cartilage and continuous inflammatory response. Here, inspired by the unique structure of synovial lipid-hyaluronic acid (HA) complex, we developed supramolecular HA-nanomedicine hydrogels for RA treatment by mediating macrophage-synovial fibroblast cross-talk through locally sustained release of celastrol (CEL). Molecular dynamics simulation confirmed that HA conjugated with hydrophobic segments could interspersed into the CEL-loaded [poly(ε-caprolactone- co -1,4,8-trioxa[4.6]spiro-9-undecanone)-poly(ethylene glycol)-poly(ε-caprolaone- co -1,4,8-trioxa[4.6]spiro-9-undecanone] (PECT) nanoparticles to form the supramolecular nanomedicine hydrogel HA-poly(ε-caprolactone- co -1,4,8-trioxa[4.6]spiro-9-un-decanone)/PECT@CEL (HP@CEL), enabling fast hydrogel formation after injection and providing a 3-dimensional environment similar with synovial region. More importantly, the controlled release of CEL from HP@CEL inhibited the macrophage polarization toward the proinflammatory M1 phenotype and further suppressed the proliferation of synovial fibroblasts by regulating the Toll-like receptor pathway. In collagen-induced arthritis model in mice, HP@CEL hydrogel treatment substantial attenuated clinical symptoms and bone erosion and improved the extracellular matrix deposition and bone regeneration in ankle joint. Altogether, such a bioinspired injectable polymer-nanomedicine hydrogel represents an effective and promising strategy for suppressing RA progression through augmenting the cross-talk of macrophages and synovial fibroblast for regulation of chronic inflammation.