A Lung-Expressing mRNA Delivery Platform with Tunable Activity in Hypoxic Environments.

Area of Science:

• Biotechnology
• Nanomedicine
• Molecular Biology

Background:

• Messenger RNA (mRNA) delivery platforms are optimized for normal oxygen levels, limiting their use in diseases affecting organs like the lungs.
• Hypoxia, or low oxygen conditions common in many diseases, significantly reduces mRNA therapy efficacy by over 80%.

Purpose of the Study:

• To develop a tunable nanoparticle platform (TULEP) for effective mRNA delivery, specifically optimized for hypoxic environments.
• To investigate the mechanism of mRNA delivery and overcome hypoxia-induced efficacy deficits.

Main Methods:

• Synthesized and characterized a novel amino acrylate polymer for creating TULEP nanoparticles with mRNA payloads.
• Evaluated TULEP's cellular association, endocytosis, endosomal escape, and protein expression in lung cells under normoxic and hypoxic conditions.
• Tuned TULEP's efficacy in hypoxia using adenosine triphosphate (ATP) and assessed *in vivo* performance in mice.

Main Results:

• Demonstrated successful mRNA complexation into TULEP nanoparticles.
• Characterized TULEP's delivery mechanism and protein expression in lung cells.
• Showcased tunable enhancement of TULEP efficacy under hypoxic conditions using ATP, with favorable *in vivo* biodistribution and tolerability in mice.

Conclusions:

• The tunable lung-expressing nanoparticle platform (TULEP) offers effective mRNA delivery, particularly in hypoxic environments.
• Highlights the importance of considering oxygen levels in the design of mRNA delivery systems for broader therapeutic applications.