Abstract 18755: Engineered Nanoparticles for the Oral Delivery of Cardioprotective Small RNA Therapeutics

• Published in: Circulation (New York, N.Y.) N.Y.), 2023-11, Vol.148 (Suppl_1)
• Main Authors: Yamaguchi, Shukuro, Miyamoto, Kazutaka, Jones, Xaviar M, Ciullo, Alessandra, Marban, Eduardo, Ibrahim, Ahmed G
• Format: Article
• Language: English
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/circ.148.suppl_1.18755

Abstract only Background: RNA drugs have been applied to cardiovascular conditions including hypercholesterolemia and amyloidosis, but such drugs are deliverable only by parenteral routes. The ability to deliver RNA drugs orally would be highly desirable. Here we describe the development of a casein-chitosan-based formulation (dubbed C2) for the oral delivery of TY1, a 24-nucleotide chemically-modified Y RNA which we are exploring as a therapeutic candidate for cardiac fibrosis. Materials and Methods: We characterized the size distribution of C2-encapsulated TY1 (C2-TY1) micelles by nanoparticle tracking analysis. qPCR quantified the number of TY1 copies per micelle, as well as the presence of exogenous RNA in intestinal tissue from animals fed C2-conjugated RNA. Using a mucin precipitation assay, we assessed the ability of C2 micelles to adsorb onto mucin. We then tested the resistance of C2-TY1 micelles to degradation through incubation with proteinase K and RNase. To assess safety, healthy animals were fed C2-TY1 (0.15mg/kg, comparable to doses effective intravenously), or vehicle (H 2 O), twice weekly and evaluated at four weeks. Finally, we gauged the therapeutic potential of orally-administered C2-TY1 in a rat model of myocardial infarction. Results: C2 micelles are 100-500 nm in size and efficiently encapsulate TY1 (~10 4 TY1 copies per particle; n=3 technical replicates). After oral gavage, C2 efficiently delivered exogenous RNA to intestinal tissue within 60 minutes, as verified by qPCR (n=9). Chitosan played a significant role in the mucoadhesive property of C2 (n=6). C2 protected TY1 from enzymatic degradation compared with other formulations (p