A Bionic Thermosensitive Sustainable Delivery System for Reversing the Progression of Osteoarthritis by Remodeling the Joint Homeostasis

Abstract Although the pathogenesis of osteoarthritis (OA) is unclear, inflammatory cytokines are related to its occurrence. However, few studies focused on the therapeutic strategies of regulating joint homeostasis by simultaneously remodeling the anti‐inflammatory and immunomodulatory microenvironments. Fibroblast growth factor 18 (FGF18) is the only disease‐modifying OA drug (DMOAD) with a potent ability and high efficiency in maintaining the phenotype of chondrocytes within cell culture models. However, its potential role in the immune microenvironment remains unknown. Besides, information on an optimal carrier, whose interface and chondral‐biomimetic microenvironment mimic the native articular tissue, is still lacking, which substantially limits the clinical efficacy of FGF18. Herein, to simulate the cartilage matrix, chondroitin sulfate (ChS)‐based nanoparticles (NPs) are integrated into poly(D, L‐lactide)‐poly(ethylene glycol)‐poly(D, L‐lactide) (PLEL) hydrogels to develop a bionic thermosensitive sustainable delivery system. Electrostatically self‐assembled ChS and ε‐poly‐l‐lysine (EPL) NPs are prepared for the bioencapsulation of FGF18. This bionic delivery system suppressed the inflammatory response in interleukin‐1β (IL‐1β)‐mediated chondrocytes, promoted macrophage M2 polarization, and inhibited M1 polarization, thereby ameliorating cartilage degeneration and synovitis in OA. Thus, the ChS‐based hydrogel system offers a potential strategy to regulate the chondrocyte‐macrophage crosstalk, thus re‐establishing the anti‐inflammatory and immunomodulatory microenvironment for OA therapy.