Inhaled RNA Therapy: From Promise to Reality

Abstract

RNA-based medicine is receiving growing attention for its diverse roles and potential therapeutic capacity. The largest obstacle in its clinical translation remains identifying a safe and effective delivery system. Studies investigating RNA therapeutics in pulmonary diseases have rapidly expanded and drug administration by inhalation allows the direct delivery of RNA therapeutics to the target site of action while minimizing systemic exposure. In this review, we highlight recent developments in pulmonary RNA delivery systems with the use of nonviral vectors. We also discuss the major knowledge gaps that require thorough investigation and provide insights that will help advance this exciting field towards the bedside.

Highlights

• Inhaled RNA therapy has great potential for treating a range of lung diseases, including lung infections, cystic fibrosis and asthma.

• Although naked RNA is able to transfect in the lung following pulmonary administration, its efficiency may be subjected to variation due to the alteration of pulmonary surfactant composition between individuals and disease status, rendering it unfavorable for clinical application.

• Many delivery systems have been generated for delivery of RNA therapeutics in the lungs.

• Hybrid delivery systems that combine polymers, lipids, or peptides are increasingly popular for RNA delivery to enhance transfection efficiency.

• Delivery systems should be tailor-made for different RNA targets and lung diseases to overcome the specific set of delivery barriers associated with the different lung diseases.

• Only a few studies have evaluated the aerosol performance, integrity of RNA following aerosolization, dose–response relationship, pharmacokinetic profile, and long-term safety of inhaled RNA therapy formulations. More effort needs to be invested in these research areas for clinical translation.