Oral Bioavailability of a Noncoding RNA Drug, TY1, That Acts on Macrophages

Area of Science:

• Biotechnology
• Pharmacology
• RNA Therapeutics

Background:

• Approved RNA therapeutics necessitate parenteral (injection) delivery methods.
• Developing oral delivery systems for RNA drugs is a significant challenge.
• Noncoding RNA (ncRNA) holds therapeutic potential but requires effective delivery.

Purpose of the Study:

• To develop and evaluate an orally bioavailable formulation for synthetic noncoding RNA (ncRNA).
• To assess the safety and efficacy of oral ncRNA delivery in preclinical models.
• To investigate the mechanism of oral ncRNA uptake and distribution.

Main Methods:

• Formulation of synthetic ncRNA (TY1) into lipid nanoparticles within casein-chitosan (C2) micelles.
• Administration of oral TY1-C2 to healthy mice to assess tolerability and toxicity.
• Evaluation of TY1-C2 in rat myocardial infarction and mouse acute lung injury models.
• Mechanistic studies involving intestinal macrophage uptake and detection of circulating monocytes.

Main Results:

• Oral TY1-C2 was well-tolerated and nontoxic in healthy mice.
• Single oral doses of TY1-C2 demonstrated cardioprotective effects in myocardial infarction and attenuated inflammation in acute lung injury.
• TY1-C2 was taken up by intestinal macrophages, with TY1 detected in circulating monocytes for up to 72 hours.
• An antisense oligonucleotide targeting hepatocytes was ineffective with C2 oral delivery, indicating formulation specificity.

Conclusions:

• The developed C2 micelle formulation enables oral delivery of bioactive ncRNA targeting macrophages.
• Oral delivery of TY1-C2 shows therapeutic potential for inflammatory conditions and tissue injury.
• This platform opens new avenues for oral RNA therapeutics, particularly for macrophage-mediated diseases.