Lung-targeted RNA delivery systems: strategies and therapeutic applications

Area of Science:

• Pulmonary medicine and drug delivery science.

Background:

• Pulmonary diseases (asthma, lung cancer, COPD, fibrosis) cause significant global health burdens.
• RNA therapeutics show promise for molecular-level disease modulation.
• Efficient, lung-specific RNA delivery is a major hurdle for clinical application.

Purpose of the Study:

• To integrate structure-function principles with clinical translation insights for pulmonary RNA delivery.
• To provide mechanistic understanding of how physicochemical parameters influence lung tropism and therapeutic efficacy.
• To identify key barriers and offer a roadmap for accelerating clinical translation of RNA therapeutics for pulmonary diseases.

Main Methods:

• Systematic examination of synthetic and biologically derived RNA carriers.
• Focus on lung-targeted delivery strategies: inhalation, intravenous, and local pulmonary administration.
• Critical analysis of clinical trial failures (e.g., ALN-RSV01, MRT-5005) to identify translation barriers.

Main Results:

• Physicochemical properties of delivery systems critically influence pulmonary tropism and efficacy.
• Inhalation, intravenous, and local administration present distinct targeting opportunities and challenges.
• Analysis of clinical failures highlights critical barriers including formulation stability, immunogenicity, and manufacturing.

Conclusions:

• Understanding structure-function relationships is key to designing effective pulmonary RNA delivery systems.
• Addressing formulation stability, immunological compatibility, and scalable manufacturing is crucial for clinical success.
• This review provides a framework for advancing RNA therapeutics for pulmonary diseases from bench to bedside.