Surface functionalization of exosomes for chondrocyte-targeted siRNA delivery and cartilage regeneration

• Published in: Journal of controlled release 2024-05, Vol.369, p.493-505
• Main Authors: Zhang, Hao, Yan, Wenjing, Wang, Jinhui, Xie, Shuqian, Tao, W. Andy, Lee, Chien-Wei, Zhang, Xing, Zhang, Guiyuan, Liu, Yufeng, Wei, Dong, Hu, Jing, Liu, Haohan, Liu, Fengying, Nie, Yamei, Chen, Xue, Xu, Hongtao, Xia, Jiang, Wang, Shizhi
• Format: Article
• Language: English
• Subjects: animal models; anterior cruciate ligament; cartilage; Cartilage regeneration; catabolism; Chondrocyte targeting; chondrocytes; collagen; disease progression; Engineered exosome; exosomes; extracellular matrix; lipids; Matrix metallopeptidase 13 (MMP13); matrix metalloproteinase 13; osteoarthritis; peptides; proteoglycans; proteomics; siRNA; therapeutics
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2024.04.009

Osteoarthritis (OA) is the most prevalent degenerative cartilage disease, but no effective treatment is currently available to ameliorate the dysregulation of cartilage catabolism. Cartilage degeneration is closely related to the change in the physiology of chondrocytes: for example, chondrocytes of the OA patients overexpress matrix metallopeptidase 13 (MMP13), a.k.a. collagenase 3, which damages the extracellular matrix (ECM) of the cartilage and deteriorate the disease progression. Inhibiting MMP13 has shown to be beneficial for OA treatments, but delivering therapeutics to the chondrocytes embedded in the dense cartilage is a challenge. Here, we engineered the exosome surface with the cartilage affinity peptide (CAP) through lipid insertion to give chondrocyte-targeting exosomes, CAP-Exo, which was then loaded with siRNA against MMP13 (siMMP13) in the interior to give CAP-Exo/siMMP13. Intra-articular administration of CAP-Exo/siMMP13 reduced the MMP13 level and increased collagen COL2A1 and proteoglycan in cartilage in a rat model of anterior cruciate ligament transection (ACLT)-induced OA. Proteomic analysis showed that CAP-Exo/siMMP13 treatment restored the altered protein levels in the IL-1β-treated chondrocytes. Taken together, a facile exosome engineering method enabled targeted delivery of siRNA to chondrocytes and chondrocyte-specific silencing of MMP13 to attenuate cartilage degeneration. [Display omitted] •Cartilage degeneration incurs osteoarthritis, a condition with no effective therapeutics currently available.•Part of the reason is the difficulty of delivering therapeutics through the dense cartilage to reach chondrocytes.•We showcase an engineering strategy to modify the lipid bilayer of exosomes and deliver siRNA against MMP13 to chondrocytes.•The chondrocyte-targeting exosomes exhibited outstanding therapeutic efficacy in treating cartilage damage in a rat model.•This exosome functionalization method may be generally applicable to devise targeted delivery for other diseases.