Inhalable extracellular vesicles as cell-free therapeutics for chronic respiratory disease

Chronic respiratory diseases, such as chronic obstructive pulmonary disease (COPD), asthma and idiopathic pulmonary fibrosis (IPF), impose a significant burden on global health. The current drugs can mostly only alleviate symptoms or delay the progression, but are not very effective in reversing the structural remodeling, and are accompanied by obvious systemic adverse reactions. Extracellular vesicles (EVs), as nanoscale membrane-bound particles released by cells, possess excellent biocompatibility, low immunogenicity, and certain tissue targeting properties. They can also partially replicate the paracrine effects of cell therapy, providing a novel drug delivery platform for precise treatment of chronic respiratory diseases, and are particularly well-suited for inhalation administration. This review first provides an overview of the molecular profiles of major classes of native EVs, including those derived from mesenchymal stromal cells, pulmonary tissues, and non-pulmonary sources such as serum or plasma, platelets, and milk, and summarizes their respective therapeutic potentials in chronic respiratory pathologies. Subsequently, the key points focus on summarizing the research progress in engineering EVs through strategies such as optimizing cultivation conditions, surface targeted modification, and loading of active substances, in order to adapt them for inhalation delivery. Finally, from the perspectives of formulation and quality control, GMP scale-up, and regulatory pathways, the opportunities and challenges of realizing the integrated transformation of cell and gene therapy through engineered inhalable EVs in chronic respiratory diseases are discussed.