Inhalable mRNA Nanoparticle with Enhanced Nebulization Stability and Pulmonary Microenvironment Infiltration

Area of Science:

• Pulmonary drug delivery
• Nanomedicine
• Gene therapy

Background:

• Messenger RNA (mRNA) delivery to the lungs is crucial for treating pulmonary diseases.
• Conventional lipid nanoparticles (LNPs) are effective for systemic delivery but struggle with pulmonary inhalation due to instability and microenvironment incompatibility.

Purpose of the Study:

• To develop and optimize lipid-based nanoparticles for efficient and safe mRNA delivery to the lungs via nebulization.
• To overcome the limitations of conventional LNPs in pulmonary delivery.

Main Methods:

• Development of an ionizable liposome-mRNA lipocomplex (iLPX) with enhanced structural stability and poly(ethylene glycol)-free composition.
• Multistep screening of iLPX formulations to select an inhalation-optimized version (IH-iLPX).
• In vivo evaluation of IH-iLPX for transfection efficiency, lung distribution, and toxicity after nebulization.

Main Results:

• The developed IH-iLPX demonstrated increased stability during nebulization compared to conventional LNPs.
• IH-iLPX exhibited superior mRNA transfection efficiency in the lungs post-inhalation.
• No observed in vivo toxicity and even protein expression in deep lung regions, targeting epithelial cells.

Conclusions:

• The novel IH-iLPX formulation is a promising platform for inhaled mRNA pulmonary therapeutics.
• This approach addresses key challenges in pulmonary mRNA delivery, enhancing stability and efficacy.
• Further development of IH-iLPX could lead to new treatments for intractable lung diseases.