Quaternization drives spleen-to-lung tropism conversion for mRNA-loaded lipid-like nanoassemblies

Area of Science:

• Biotechnology
• Nanomedicine
• Drug Delivery Systems

Background:

• Current messenger RNA (mRNA) delivery systems predominantly accumulate in the liver.
• There is a growing need for non-liver mRNA delivery platforms for targeted therapies.
• Developing alternative delivery systems is crucial for expanding mRNA's therapeutic potential.

Purpose of the Study:

• To create novel cationic lipid-like nanoassemblies using a N-quaternizing strategy.
• To evaluate the physicochemical properties and in vitro mRNA delivery efficiency of these nanoassemblies.
• To investigate the organ tropism and lung-targeting capabilities of the modified nanoassemblies in vivo.

Main Methods:

• Preparation of cationic lipid-like nanoassemblies via N-quaternization.
• Assessment of physicochemical characteristics, including stability over time.
• In vitro evaluation of mRNA delivery and translation efficiency.
• In vivo organ tropism studies in mice following intravenous administration.

Main Results:

• Quaternization enhanced in vitro mRNA delivery performance.
• The nanoassemblies demonstrated a shift in organ tropism from the spleen to the lung.
• Achieved over 95% exogenous mRNA translation in lung tissues, primarily in pulmonary immune cells.
• The developed carriers maintained stability for over one year at ambient temperature.

Conclusions:

• Quaternization is an effective strategy for creating lung-targeted mRNA delivery systems.
• This approach bypasses the need for specific targeting ligands.
• These lung-specific mRNA delivery systems hold promise for treating various lung diseases.