Unpacking the anti-fibrotic arsenal: molecular mechanisms and therapeutic translation of MSC-derived exosomes in pulmonary fibrosis

Pulmonary fibrosis (PF) is a progressive, fatal interstitial lung disease with a dire prognosis and limited therapeutic options. Current standard-of-care anti-fibrotic agents (e.g., nintedanib and pirfenidone) offer only modest efficacy in slowing disease progression. Mesenchymal stem cell-derived exosomes (MSC-Exos) have recently emerged as a promising cell-free therapeutic strategy, boasting superior biocompatibility, low immunogenicity, enhanced biodistribution, and an innate tropism for injured tissues. Their potent anti-fibrotic effects are mediated through multiple mechanisms: targeted homing to fibrotic niches; reprogramming of dysregulated immune responses, notably by shifting macrophage polarization from a pro-inflammatory (M1) to an anti-inflammatory/reparative (M2) phenotype; suppression of pathological extracellular matrix deposition via inhibition of core fibrogenic pathways; and alleviation of endoplasmic reticulum stress in alveolar epithelial cells. This review systematically delineates the biological functions and molecular mechanisms underpinning the therapeutic actions of MSC-Exos in PF. We further evaluate completed and ongoing clinical trials (2014-2024), appraise the current translational landscape, and identify persistent challenges in drug development. Ultimately, this integrative analysis aims to define the mechanistic basis of MSC-Exos' efficacy, evaluate their clinical trajectory, and provide a strategic roadmap for their development into precision nanotherapeutics for PF.