Effect Analysis of Extracellular Vesicles in the Treatment of Bronchopulmonary Dysplasia via Different Drug Delivery and Administration Routes

Abstract: Extracellular vesicles (EVs) are emerging as nanoscale, cell-free therapeutics for bronchopulmonary dysplasia (BPD), a chronic lung disease in premature infants characterized by underdeveloped alveoli and abnormal blood vessel formation. This review exhibits how different EV delivery methods influence therapeutic effects in BPD. Intra-tracheal administration of EVs enables localized pulmonary delivery, which may improve treatment efficiency via reducing inflammation and promoting lung development. Intravenous delivery provides systemic anti-inflammatory effects requiring higher doses because of lung’s blood vessel barriers. Intraperitoneal administration requires higher dosages to produce comparable effects and shows lower drug accumulation in the lungs. Intragastric administration often results in poor absorption due to the digestive environment. The distribution of EVs in the body is largely dependent on delivery methods. Nebulized and tracheal administrated EVs primarily concentrate in the lungs, whereas intravenous EVs tend to distribute in the liver and spleen. Mechanistically, EVs reduce oxidative stress and cell damage by influencing important biological pathways like TGF-β 1/Smad3 and PTEN/PI3K/Akt. Although previous studies in neonatal animal models demonstrated that EVs are safe and promising, clinical translation of EVs requires standardized production, optimized dosage, non-invasive administration method, and long-term safety verification. Future efforts are suggested to focus on neonate targeting, biomarker-guided clinical trials of EVs in treating BPD. Plain Language Summary: Premature infants with bronchopulmonary dysplasia (BPD) experience chronic lung impairment, characterized by impaired lung development and persistent inflammation. Current therapeutic options for these infants are limited and may be associated with adverse effects. Extracellular vesicles are tiny particles released by cells, which have demonstrated potential in treating BPD in preclinical studies. This review compares different methods of delivering EVs, including intratracheal inhalation, intravenous injection, intraperitoneal injection, and oral-intragastric routes. Inhalation of EVs targets the lungs of affected infants, reducing inflammation and supporting alveolar development. Intraperitoneal delivery is less effective than intravenous injection, which requires larger doses but has anti-inflammatory effects throughout the body. Oral administration of EVs poses challenges for infants due to intestinal degradation. By transporting molecules (eg proteins, miRNAs) that guard against damaging pathways and restore lung tissue. In spite of promising preclinical results, further research is required to examine EV production, dosages, and safety before clinical use in premature infants. Future researches are suggested to focus on developing EVs for non-invasive targeted delivery, pharmacokinetic modeling specific to neonates, and biomarker-driven trials to treat BPD. Keywords: extracellular vesicle, bronchopulmonary dysplasia, drug delivery, administration routes