Non-viral mRNA delivery to the lungs

Abstract

The rapid advancement of mRNA therapeutics, exemplified by COVID-19 vaccines, underscores the transformative potential of non-viral delivery systems. However, achieving efficient and targeted mRNA delivery to the lungs remains a critical challenge due to biological barriers such as pulmonary mucus, nanoparticle instability, and off-target accumulation particularly in the liver. Addressing these challenges is crucial for advancing treatments for respiratory diseases, including cystic fibrosis, primary ciliary dyskinesia, and lung cancers. This review highlights emerging strategies to enhance lung-targeted mRNA delivery, focusing on lipid nanoparticles, polymeric nanoparticles, lipid–polymer hybrids, and peptide/protein conjugates. By discussing advances in bioinspired design and nanoparticle reformulation, this review provides a roadmap for overcoming current delivery limitations and accelerating the clinical translation of lung-targeted mRNA therapies.