Oral Bioavailability of a Noncoding RNA Drug, TY1, That Acts on Macrophages.
Publication Year:
2025
PubMed ID:
40823342
Funding Grants:
Public Summary:
Currently, RNA drugs must be injected because digestion destroys them, but scientists have developed a special protective shell that allows these medicines to be taken by mouth. Once swallowed, the protected medicine survives the stomach and is absorbed by immune cells in the gut, which act like tiny delivery trucks carrying the drug through the bloodstream for up to three days. In animal trials, a single oral dose of an anti-inflammatory RNA drug successfully protected hearts after a heart attack and reduced lung inflammation just as effectively as a traditional injection. While this specific method only works for drugs designed to target the immune system—since it relies on those gut immune cells for transport—this breakthrough paves the way for easy-to-swallow pill treatments for a wide variety of inflammatory diseases.
Scientific Abstract:
All approved RNA therapeutics require parenteral delivery. Here, we demonstrate an orally bioavailable formulation wherein synthetic noncoding (nc) RNA, packaged into lipid nanoparticles, is loaded into casein-chitosan (C2) micelles. We used the C2 formulation to deliver TY1, a 24-nucleotide synthetic ncRNA, which targets DNA damage and attenuates inflammation in macrophages. C2-formulated TY1 (TY1(C2)) efficiently packages and protects TY1 against degradative enzymes. In healthy mice, oral TY1(C2) was well-tolerated and nontoxic. Oral TY1(C2) exhibited disease-modifying bioactivity in two models of tissue injury: (1) rat myocardial infarction, where a single oral dose of TY1(C2) was cardioprotective, on par with intravenously-delivered TY1; and (2) mouse acute lung injury, where a single dose of TY1(C2) attenuated pulmonary inflammation. Mechanistic dissection revealed that TY1(C2) is taken up by intestinal macrophages, namely those of the lamina propria and Peyer's patches. Afterwards, TY1 could be detected in circulating monocytes for up to 72 h post-ingestion. Unlike TY1, which acts on macrophages, an antisense oligonucleotide against Factor VII, which acts on hepatocytes, is not effective when administered in the C2 formulation. Thus, not all ncRNA drugs are bioactive when delivered by mouth. Oral delivery of macrophage-active RNA opens up a wide range of potential new therapeutic opportunities.