Injectable Silk Fibroin-Based Hydrogels with Ultrafast <i>In Situ</i> Gelation via an Unfolding-Aggregating Strategy for Osteoarthritis Treatment

Intra-articular injection of hydrogel-based nanodrug delivery systems is receiving considerable attention for the treatment of osteoarthritis (OA). Nevertheless, its therapeutic efficacy and reliability are severely hindered by fabrication procedures and gelation kinetics, which subsequently exert significant influence on the retention efficiency and bioavailability of therapeutic nanodrugs within the articular cavity. In this study, the utilization of a surfactant-induced unfolding-aggregating assembly strategy is proposed to develop an injectable silk fibroin (SF)-based hydrogel as a dual-drug delivery system for OA treatment, fulfilling the demands of an easy fabrication process, ultrafast <i>in situ</i> gelation, and effective therapeutic outcomes. Under the induction of benzyldodecyldimethylammonium bromide (BDAB), SF molecules initially undergo unfolding from the native state to expose hydrophobic chain segments and then initiate the nucleation and aggregation of β-sheet structures, obviously reducing the energy barrier to achieve <i>in situ</i> gelation within 4 s. Furthermore, the BDAB-induced ultrafast <i>in situ</i> gelation technique is exploited to load core-shell nanodrugs consisting of methotrexate and chondroitin sulfate, thereby modulating M1/M2 macrophage repolarization and protecting chondrocytes from inflammatory invasion. <i>In vivo</i> rat OA models demonstrate that this injectable hydrogel system significantly suppresses the pathological progression of OA and promotes cartilage repair, supporting its potential clinical applications in the treatment of cartilage-related diseases.