# Synovial inflammatory macrophage-derived extracellular vesicles exacerbate cartilage lesions with a FMRP-selectively sorted manner in osteoarthritis

## TL;DR

This study shows that inflammatory macrophage-derived extracellular vesicles worsen cartilage damage in osteoarthritis and suggests a new treatment strategy using engineered vesicles.

## Contribution

The study introduces engineered extracellular vesicles targeting synovial macrophages as a novel therapeutic approach for osteoarthritis.

## Key findings

- EVs from pro-inflammatory macrophages accelerate cartilage degeneration by suppressing autophagy via miR-155-5p.
- Deleting miR-155 in macrophages reduces cartilage lesions and synovitis in OA mice.
- FMRP selectively sorts miR-155-5p into EVs, and plasma EVs FMRP levels correlate with OA progression.

## Abstract

Osteoarthritis (OA) is an aging-related degenerative joint disease without effective therapies. In the early stage of OA, mild synovitis has been reported to induce cartilage lesions. A better understanding of crosstalk between synovial macrophages and chondrocytes are being developed to discover new OA therapeutics. Here, we identified that the extracellular vesicles (EVs) derived from synovial pro-inflammatory macrophages regulated the autophagy function of chondrocytes, induced the onset of cartilage degeneration in normal joints. Mechanistically, the active transfer of miR-155-5p via EVs from synovial pro-inflammatory macrophages to chondrocytes accelerates cartilage degeneration by suppressing GSK-3β/mTORC1 axis-mediated autophagy function during OA progression. Deleting miR-155 from synovial pro-inflammatory macrophages relieved cartilage lesions and synovitis in OA mice. On the other hand, Fragile X mental retardation protein (FMRP) selectively sorted miR-155-5p into EVs derived from synovial pro-inflammatory macrophages, and the levels of plasma EVs FMRP were closely related to OA progression, suggesting the potential candidate for diagnostic OA biomarkers. Based on these findings, we developed engineering EVs with MAP (pro-inflammatory macrophages-affinity peptide) derived from adipose-derived stromal cells (ADSCs) as the antagomiR-155-5p delivery vehicles which exhibited superior therapeutic effects on synovitis and injured cartilage in the surgery-induced OA rats. Furthermore, MAP-ADSCs-EVs were proved to target the polarization of synovial pro-inflammatory macrophages in the clinical OA samples. Collectively, our study indicates that plasma EVs FMRP and engineered MAP-ADSCs-EVs targeting synovial pro-inflammatory macrophages represent potential novel therapeutic strategy for the progression of OA.