Dual metabolic-inflammation modulation in MicroRNA@neutrophil-derived microvesicles achieve robust osteoarthritis therapy

作者：Yijun Chen, Yongbin Wang, Ruonan Yan, Yichen Liu, Yupeng Dai, Lingjing Xue, Caoyun Ju, Can Zhang · 发表于：Acta Pharmaceutica Sinica B · 年份：2025 · DOI：10.1016/j.apsb.2025.09.020 · 被引用次数：3 · 研究领域：Extracellular vesicles in disease、Osteoarthritis Treatment and Mechanisms、Bone and Joint Diseases

Osteoarthritis (OA) presents significant therapeutic challenges due to the irreversible cartilage loss driven by chondrocyte metabolic imbalance and a severe inflammatory microenvironment. Conventional treatments are limited by poor chondrocyte-targeting and ineffectiveness of single-target medication. Here, we develop an anti-inflammatory neutrophil-derived microvesicle (MV)-based gene therapy for OA treatment, which leverages the intrinsic cartilage-penetrating capabilities of MVs to improve the targeted delivery of microRNA-140-5p (miR140) to chondrocytes, and the synergistic effect of anti-inflammatory MVs and miR140 to dual modulate the metabolic homeostasis of chondrocytes and the inflamed microenvironment. We demonstrate that miR140@MVs not only alleviate synovial inflammation via reprogramming the phenotypes of macrophages and adsorbing inflammatory factors, but also restore normal cartilage thickness in a destabilized medial meniscus mouse model due to the rebuilt metabolic homeostasis of chondrocytes, thus gaining a remarkable therapeutic effect up to 28 days. This study provides an immuno-stimulation method for production of anti-inflammatory MVs, and puts forward a safe and effective MVs-based miRNA system for treatment of joint-related diseases.