Work

M2 Macrophage‐Derived Small Extracellular Vesicle miR‐106a‐Loaded QCG Hydrogel Targets the RNF128‐LXR Pathway to Reprogram Chondrocyte Cholesterol Metabolism for Osteoarthritis Therapy

Year: 2026

Type: article

Abstract: This study addresses osteoarthritis (OA), in which dysregulated chondrocyte cholesterol homeostasis and cellular senescence contribute to cartilage degeneration, by developing an inflammation-responsive injectable QCG hydrogel for local delivery of miR-106a-enriched M2 macrophage-derived small extracellular vesicles (sEVs). The QCG hydrogel was constructed from quaternized chitosan (QCS) and 4-carboxyphenylboronic acid-gelatin (CPBA-gelatin) and loaded with miR-106a-enriched M2-sEVs (QCG@sEV-miR-106a). M2-sEVs were isolated by differential ultracentrifugation and characterized by transmission electron microscopy, nanoparticle tracking analysis, and vesicle-associated protein markers. High-throughput miRNA profiling and chondrocyte RNA sequencing identified miR-106a as a candidate regulatory molecule, and RNF128 was confirmed as a direct target by dual-luciferase reporter assay. Functional experiments showed that miR-106a suppresses RNF128, thereby promoting chondrocyte proliferation and extracellular matrix synthesis while attenuating senescence. Exploratory proteomic screening suggested RNF128-associated changes in cholesterol- and lysosome-related processes, whereas independent molecular and functional assays demonstrated that RNF128 promotes LXRα ubiquitination and proteasome-dependent degradation, suppresses LXR signaling, and disrupts cholesterol homeostasis. In a destabilization of the medial meniscus (DMM)-induced OA rat model, QCG@sEV-miR-106a showed ROS-responsive release, prolonged intra-articular retention for up to 22 days, reduced cartilage degeneration and matrix loss, improved pain-related behaviors, and favorable short-term biocompatibility. Together, these findings support a local biomaterial delivery strategy in which miR-106a-mediated RNF128 inhibition preserves LXR signaling and cholesterol homeostasis to attenuate OA-associated chondrocyte senescence.

Source: Journal of Extracellular Vesicles

DOI: 10.1002/jev2.70386

Authors: Baozhe Liu, Zhan Wang, Jingyong Zhang, Wei Du, Lifeng Ding, Shang Piao

Institutions: Sheng Jing Hospital, Liaoning Cancer Hospital & Institute, China Medical University

Language: English

Topic: Osteoarthritis Treatment and Mechanisms

Subfield: Rheumatology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $4,410