Cartilage-targeting engineered probiotic bacterial extracellular vesicles treat osteoarthritis through modulation of matrix homeostasis.

Reversing extracellular matrix (ECM) metabolic dysregulation to facilitate cartilage repair represents a key therapeutic strategy for osteoarthritis (OA) treatment. Owing to the avascular nature of joint structures, intra-articular injection is a commonly used clinical administration route. However, the current drug retention time is insufficient to effectively reverse OA progression. In this study, we demonstrated that natural bacterial extracellular vesicles (BEVs) are capable of repairing cartilage damage. We modified Lactobacillus rhamnosus GG (LGG)-derived BEVs with a chondrocyte-targeting peptide to prolong their therapeutic efficacy. Engineered BEVs, as a drug delivery system, are capable of continuously transporting endogenous miRNAs. Cartilage-targeting LGG-EVs (W-LGG-EVs) penetrate deeply into cartilage tissue and promote extracellular matrix secretion by chondrocytes. Furthermore, W-LGG-EVs were shown to restore cartilage homeostasis and ultimately alleviate stress-related OA. BEVs, as a novel and safe therapeutic agent, hold clinical feasibility.