Engineered Exosomes with ATF5-Modified mRNA Loaded in Injectable Thermogels Alleviate Osteoarthritis by Targeting the Mitochondrial Unfolded Protein Response

作者：Tiancong Ma, Guangyu Xu, Tian Gao, Guanglei Zhao, Gangyong Huang, Jingsheng Shi, Jie Chen, Jian Song, Jun Xia, Xiaosheng Ma · 发表于：ACS Applied Materials & Interfaces · 年份：2024 · DOI：10.1021/acsami.3c17209 · 被引用次数：40 · 研究领域：RNA Interference and Gene Delivery、Osteoarthritis Treatment and Mechanisms、Extracellular vesicles in disease

Osteoarthritis (OA) progression is highly associated with chondrocyte mitochondrial dysfunction and disorders of catabolism and anabolism of the extracellular matrix (ECM) in the articular cartilage. The mitochondrial unfolded protein response (UPR mt ), which is an integral component of the mitochondrial quality control (MQC) system, is essential for maintaining chondrocyte homeostasis. We successfully validated the pivotal role of activating transcription factor 5 (ATF5) in upregulating the UPR mt, mitigating IL-1β-induced inflammation and mitochondrial dysfunction, and promoting balanced metabolism in articular cartilage ECM, proving its potential as a promising therapeutic target for OA. Modified mRNAs (modRNAs) have emerged as novel and efficient gene delivery vectors for nucleic acid therapeutic approaches. In this study, we combined Atf5-modRNA (modAtf5) with engineered exosomes derived from bone mesenchymal stem cells (Ex modAtf5 ) to exert cytoprotective effects on chondrocytes in articular cartilage via Atf5. However, the rapid localized metabolization of Ex modAtf5 limits its application. PLGA–PEG-PLGA (Gel), an injectable thermosensitive hydrogel, was used as a carrier of Ex modAtf5 (Gel@Ex modAtf5 ) to achieve a sustained release of Ex modAtf5 . In vitro and in vivo, the use of Gel@Ex modAtf5 was shown to be a highly effective strategy for OA treatment. The in vivo therapeutic effect of Gel@Ex modAtf5 was evidenced by the preservation of the intact cartilage surf...