Unlocking the potential of engineered exosomes for knee osteoarthritis therapy.

Knee osteoarthritis (KOA) is a common age-related degenerative joint disease. Currently, there is a lack of effective treatments capable of altering its progression. Exosomes, as key mediators of intercellular communication, possess innate biocompatibility, low immunogenicity, and favorable barrier-penetrating capabilities, demonstrating potential in modulating the joint microenvironment. However, natural exosomes face challenges such as poor targeting specificity, limited drug-loading capacity, and a short half-life. To address these limitations, engineered exosomes have been developed through strategies including surface modification, drug-loading optimization, and integration with biomaterials, significantly enhancing their therapeutic efficacy in preclinical models. This review summarizes recent advances in the application of engineered exosomes for KOA treatment, with a focus on elucidating their molecular mechanisms in inhibiting inflammation, regulating chondrocyte function, maintaining extracellular matrix (ECM) homeostasis, modulating subchondral bone remodeling, and influencing pain pathways. Although preclinical studies have demonstrated promising therapeutic outcomes, the clinical translation of engineered exosomes still faces challenges, including standardized production, safety evaluation, optimization of targeting efficiency, and validation in large animal models. While Phase I safety data are available, the field currently lacks Phase II efficacy data or disease-modifying proof. Therefore, engineered exosomes represent a promising preclinical candidate requiring further validation through Phase II/III trials. Future research should focus on deepening mechanistic understanding, standardizing production processes, and conducting rigorous clinical trials to establish engineered exosomes as a viable therapeutic option for KOA.