Mechanical loading primes MSC-derived exosomes to promote cartilage repair.

Abstract

Cartilage defects remain a major clinical challenge due to the limited efficacy of current therapies and the intrinsically low regenerative capacity of chondrocytes. Mechanical loading has emerged as a promising strategy to enhance stem cell-based cartilage repair; however, the underlying molecular mechanisms remain poorly understood. Here, we show that cyclic tensile strain primes mesenchymal stem cells (MSCs) to secrete exosomes enriched in microRNA-330-3p (<i>miR-330-3p</i>), which markedly enhances cartilage regeneration. Mechanistically, <i>miR-330-3p</i> restores mitochondrial quality control in chondrocytes by engaging an FKBP4-FoxO3a-dependent mitophagy program, leading to activation of PINK1/Parkin-mediated mitochondrial clearance. The regenerative efficacy of <i>miR-330-3p-</i>enriched exosomes was validated in a Sprague-Dawley rat model of cartilage defects. <i>In vitro</i>, <i>miR-330-3p</i> promotes chondrocyte proliferation and migration while suppressing apoptosis, senescence, and extracellular matrix degradation. Together, these findings identify mechanically primed MSC-derived exosomes as a mechanistically informed therapeutic strategy for cartilage repair.