Engineerable mesenchymal stem cell-derived extracellular vesicles as promising therapeutic strategies for pulmonary fibrosis
Ye Chen, Moxuan Li, Juntao Yang, Yuqi Chen, Jiancheng Wang
Abstract
Pulmonary fibrosis (PF) is a progressive and fatal interstitial lung disease characterized by fibroblast activation, excessive extracellular matrix deposition, and irreversible lung damage. Current therapeutic interventions, including anti-fibrotic medications and lung transplantation, are constrained by limited efficacy, adverse side effects, and logistical challenges. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have emerged as a promising cell-free therapeutic approach due to their safety, scalability, and capacity to deliver bioactive cargo. These nano-sized vesicles replicate the regenerative and immunomodulatory properties of their parent cells, targeting dysregulated signaling pathways and pathological cellular phenotypes associated with PF. MSC-EVs modulate fibrosis by restoring alveolar epithelial cell function, suppressing myofibroblast activation, and regulating immune responses, such as macrophage polarization and neutrophil infiltration. However, challenges such as limited clinical efficacy and insufficient targeting hinder the broad application of MSC-EVs. Engineering strategies like preconditioning, drug loading, and surface modification can solve the above issues. Our review synthesizes PubMed/Google Scholar literature up to Feb. 2025 on MSC-EVs’ targeted PF therapy and engineering strategies, aiming to translate preclinical insights into clinical use. Extracellular vesicles (EVs), particularly exosomes, have evolved from being initially regarded as cellular “waste” to becoming a cornerstone of regenerative medicine. Their ability to transfer bioactive molecules—such as miRNAs, proteins, and lipids—has revolutionized therapeutic strategies across multiple organ systems, including the heart, liver, and kidneys. The lung, however, presents a unique therapeutic niche for EVs. Intravenously administered EVs naturally accumulate in pulmonary tissues due to the lung’s extensive capillary network and first-pass filtration effect, making it an ideal target for EV-based therapies. Furthermore, rising global air pollution and associated respiratory pathologies underscore the urgent need for innovative treatments for lung diseases. Our focus on pulmonary fibrosis aligns with these clinical and anatomical advantages, positioning mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) as a promising cell-free therapeutic avenue.