Extracellular vesicles (EVs), including exosomes and microvesicles, have emerged as pivotal mediators of intercellular communication, carrying bioactive molecules such as proteins, lipids, and nucleic acids. In neonatology, the clinical application of EVs is gaining attention for their diagnostic and therapeutic potential across a range of diseases including neonatal sepsis, bronchopulmonary dysplasia, hypoxic-ischemic encephalopathy, and necrotizing enterocolitis. EVs derived from stem cells or immune cells have demonstrated anti-inflammatory, immunomodulatory, and regenerative properties in preclinical models. Additionally, EVs present novel opportunities for non-invasive biomarker discovery, facilitating early disease detection and monitoring. Despite promising outcomes, clinical translation requires standardized isolation methods, safety validation, and robust clinical trials. This speech summarizes the current landscape of EV-based strategies in neonatal care and outlines future directions for their integration into clinical practice.

Bronchopulmonary dysplasia (BPD) is a chronic lung disease predominantly affecting premature infants. It manifests in two forms: the “classic” BPD, which results from lung injury due to prolonged oxygen therapy and mechanical ventilation, and the “new” BPD, seen in extremely low birth weight infants despite surfactant therapy. The latter is characterized by disrupted lung development, including abnormal alveolar and vascular formation, elastin dysregulation, smooth muscle proliferation, persistent inflammation, and pulmonary edema.

BPD pathogenesis is multifactorial, involving oxidative stress, surfactant deficiency, mechanical ventilation, infections, malnutrition, and hemodynamic instability such as patent ductus arteriosus. Current treatment strategies—including respiratory support, medications, and nutritional care—are often limited in efficacy and may carry adverse effects.

Stem-cell-based therapies, especially those utilizing mesenchymal stem cells (MSCs) and MSC-derived extracellular vesicles (EVs), have demonstrated promise in preclinical models. These approaches can reduce inflammation, improve alveolarization, attenuate fibrosis, and potentially improve survival. However, several barriers must be overcome before clinical application, including optimal cell source, dosing, delivery method, safety, consistency, and ethical considerations.

Recent efforts focus on enhancing MSC efficacy through modulation of culture conditions, hypoxia, genetic engineering, and preconditioning strategies to improve their anti-inflammatory, immunomodulatory, and regenerative capabilities. These advances aim to optimize MSC viability, homing, differentiation, and therapeutic potential in BPD.

Updated Summary: Bronchopulmonary Dysplasia and Advances in Extracellular Vesicle-Based Therapy (2023–2025)
Bronchopulmonary dysplasia (BPD) is a chronic lung disease primarily affecting premature infants. It is classified into “classic” and “new” forms. The classic form results from oxygen toxicity and prolonged mechanical ventilation, leading to alveolar simplification and fibrosis. In contrast, the “new” BPD, seen in extremely low birth weight infants despite surfactant therapy, is caused by disrupted lung development and characterized by abnormal alveolarization, impaired vascularization, disorganized elastin deposition, increased smooth muscle growth, chronic inflammation, and pulmonary edema.

The pathogenesis of BPD is multifactorial and involves oxidative stress, surfactant deficiency, mechanical injury, infection, malnutrition, and patent ductus arteriosus. Existing treatments—including respiratory support, bronchodilators, corticosteroids, diuretics, sildenafil, and nutritional support—are often only modestly effective and carry significant side effects.

Recent Advances in EV-Based Therapy
Extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) have gained attention as a promising cell-free regenerative strategy for BPD. Key findings from the past two years include:

Improved lung architecture and function in animal models: Intravenous delivery of human bone marrow MSC-derived EVs in ventilated preterm lambs significantly improved lung structure (e.g., alveolarization and capillary density), decreased pulmonary hypertension markers, and increased VEGFR2 expression.

hiPSC-derived EVs support lung repair: In fetal rat lung explants, EVs from human-induced pluripotent stem cells (hiPSCs) and their lung progenitor derivatives promoted alveolar morphogenesis and upregulated antioxidant genes (e.g., Nfe2l2, Prdx5) under hyperoxic stress.

Lung-brain axis and systemic EV effects: EVs released from alveolar macrophages of preterm infants exposed to high oxygen, containing apoptosis-associated speck-like protein (ASC), can cross the blood-brain barrier and contribute to inflammation and cell death in both the lungs and hippocampus in mice, implicating a potential role in neurodevelopmental comorbidities.

Biomarker potential of airway EVs: EVs isolated from tracheal aspirates of preterm infants (22–35 weeks gestation) showed distinct size profiles and surface markers (e.g., CD24, CD14) associated with gestational age and BPD severity, suggesting diagnostic potential.

Wharton’s Jelly-derived EVs outperform bone marrow EVs: In rodent models of BPD and pulmonary hypertension, early single-dose administration of umbilical cord-derived MSC-EVs (via IV or intratracheal routes) showed long-lasting protective effects on alveolar and vascular development, surpassing bone marrow EVs in efficacy.

Strategies to enhance EV efficacy: Ongoing research focuses on improving EV therapeutic potential through hypoxic preconditioning, genetic modification, immune receptor priming, optimized culture conditions, and advanced delivery methods.

Conclusion
Stem-cell-derived EVs represent a novel and promising therapeutic approach for BPD by modulating inflammation, enhancing lung repair, and potentially improving survival. Emerging evidence highlights not only their local pulmonary benefits but also systemic implications via the lung-brain axis. While results in preclinical models are compelling, further research is essential to define optimal dosing, timing, safety, and manufacturing standards before clinical translation.