Artificial Cell-Derived Vesicles: Extracellular Vesicle Mimetics for Chondrocyte Restoration in TMJOA Therapy

Yu Hu,1,* Guobin Huang,2,3,* Zichao Dai,2,3 Rongqiang Yang,2,3 Yang Zhang,4 Yelin Zhang,2,3 Huilin Shen,2,3 Zhu Pu,2,3 Liya Ma,2,3 Song Li2,3 1Outpatient Department, Kunming Medical University School and Hospital of Stomatology, Kunming, 650106, People’s Republic of China; 2Yunnan Key Laboratory of Stomatology, Kunming, 650106, People’s Republic of China; 3Department of Dental Research, Kunming Medical University School and Hospital of Stomatology, Kunming, 650106, People’s Republic of China; 4Stomatology Center of Baoshan People’s Hospital, Baoshan, Yunnan, 678000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Liya Ma, Email [email protected] Song Li, Email [email protected]: Cartilage repair in temporomandibular joint osteoarthritis (TMJOA) remains a clinical challenge. Despite the strong repair potential of extracellular vesicles (EVs), their clinical use is constrained by yield and purification issues. This study explores artificial cell-derived vesicles (ACDVs) as a novel acellular strategy for cartilage repair, providing a promising alternative to EVs.Methods: EVs and ACDVs were isolated from umbilical cord mesenchymal stem cells, and their particle number and protein yield were compared. Mandibular condylar chondrocytes (MCCs) were treated with EVs/ACDVs after IL-1β stimulation to assess their effects on MCC apoptosis, proliferation, migration, and chondrogenic differentiation. Transcriptomic analysis was conducted to explore the therapeutic mechanisms of ACDVs. In a rat TMJOA model, local ACDV injection was evaluated for its effects on cartilage matrix synthesis and subchondral bone repair.Results: ACDVs resembled EVs in morphology and particle size, but exhibited significantly higher particle counts and protein yields. Efficiently internalized by MCCs, ACDVs effectively mitigated IL-1β-induced apoptosis, while promoting MCC proliferation, migration, and chondrogenic differentiation. This effect was likely mediated by the activation of genes involved in extracellular matrix synthesis. In a rat model of TMJOA, local ACDV injection ameliorated subchondral bone damage and stimulated cartilage matrix synthesis.Conclusion: This study demonstrates that ACDVs, generated by stepwise extrusion, are produced at significantly higher yields than EVs and show equal or superior efficacy in cartilage matrix repair. These findings endorse ACDVs as a promising alternative to EVs for disease therapy and drug delivery.Keywords: artificial cell-derived vesicles, extrusion-derived vesicles, temporomandibular joint osteoarthritis, chondrocytes