Advances in mRNA-LNP lung-targeted delivery strategies

The lung, a vital organ for homeostasis, is vulnerable to various diseases that challenge healthcare systems due to limited treatment options. Fortunately, mRNA-based gene therapy offers a promising solution, demonstrating high efficiency and safety across applications in vaccines, protein replacement therapy, and cancer treatment. However, naked mRNA faces challenges like degradation, poor cell penetration, and immunogenicity. The lung's complex structure further complicates mRNA delivery. In this way, lipid nanoparticles (LNPs) have emerged as an effective solution, demonstrated by their success in COVID-19 mRNA vaccines through superior encapsulation and biocompatibility. Extensive researches focus on developing LNP-based pulmonary mRNA delivery systems for treating viral infections and lung diseases. This review analyzes the current state and developments in mRNA-LNP applications for pulmonary diseases and LNP-based strategies for lung-targeted mRNA delivery. We explore the optimization and development of LNP platforms across four administration routes: nebulized inhalation, intratracheal administration, nasal administration, and systemic administration. Our goal is to provide researchers with a comprehensive reference covering both fundamental principles and cutting-edge developments in pulmonary mRNA-LNP delivery systems.