Remodeling the Proinflammatory Microenvironment in Osteoarthritis through Interleukin-1 Beta Tailored Exosome Cargo for Inflammatory Regulation and Cartilage Regeneration
Manyu Chen, Yuhan Liu, Yi Cao, Chengkun Zhao, Quanying Liu, Na Li, Yuan Liu, Xiaolin Cui, Pengcheng Liu, Jie Liang, Yujiang Fan, Qiguang Wang, Xingdong Zhang
Abstract
Osteoarthritis (OA) presents a significant therapeutic challenge, with few options for preserving joint cartilage and repairing associated tissue damage. Inflammation is a pivotal factor in OA-induced cartilage deterioration and synovial inflammation. Recently, exosomes derived from human umbilical cord mesenchymal stem cells (HucMSCs) have gained recognition as a promising noncellular therapeutic modality, but their use is hindered by the challenge of harvesting a sufficient number of exosomes with effective therapeutic efficacy. Given that HucMSCs are highly sensitive to microenvironmental signals, we hypothesized that priming HucMSCs within a proinflammatory environment would increase the number of exosomes secreted with enhanced anti-inflammatory properties. Subsequent miRNA profiling and pathway analysis confirmed that interleukin-1 beta (IL-1β)-induced exosomes (C-Exos) exert positive effects through miRNA regulation and signaling pathway modulation. In vitro experiments revealed that C-Exos enhance chondrocyte functionality and cartilage matrix production, as well as macrophage polarization, thereby enhancing cartilage repair. C-Exos were encapsulated in hyaluronic acid hydrogel microspheres (HMs) to ensure sustained release, leading to substantial improvements in the inflammatory microenvironment and cartilage regeneration in a rat OA model. This study outlines a strategy to tailor exosome cargo for anti-inflammatory and cartilage regenerative purposes, with the functionalized HMs demonstrating potential for OA treatment.