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Systemic delivery of biotherapeutic RNA to the myocardium transiently modulates cardiac contractility in vivo

The heart is a particularly challenging target for gene therapy and nucleotide-based therapeutics. Drugs administered intravenously are hindered by hepatic uptake and fail to accumulate in the heart. This recent article published in PNAS describes the efficacy of cardiotropic lipid nanoparticles (cLNPs) to deliver RNA cargo to the myocardium. To minimize delivery to and accumulation in the liver, the authors used either ApoE knockout rodents or siRNA-mediated knockdown of ApoE expression in wild type mice. Next, to address the efficacy of intravenous administration of cLNPS, they generated an siRNA against SERCA2A and evaluated cardiac delivery by monitoring SERCA2A protein over a 5 day period. To evaluate cardiomyocyte function, they isolated cardiomyocytes when SERCA2A proteins were lowest (day 3) and measured contractile performance, noting significantly diminished fractional shortening as well as shortening and re-lengthening velocities. Shortening and re-lengthening times (times to 50% peak and baseline) weren’t significantly altered. Taken together, their data demonstrate the potential for cLNP-mediated delivery of nucleotide-based therapeutics.

To validate and evaluate the delivery of their siRNA intervention, the authors utilized an IonOptix MultiCell System equipped with our CytoMotion and SarcLen acquisition modules for data acquisition and CytoSolver for data analysis. Like our Calcium and Contractility and CytoMotion Lite Systems, IonOptix MultiCell Systems provide reliable high content data characterizing cardiomyocyte function and performance.

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Shuvaev VV, Tam YK, Lee BW, Myerson JW, Herbst A, Kiseleva RY, Glassman PM, Parhiz H, Alameh MG, Pardi N, Muramatsu H, Shuvaeva TI, Arguiri E, Marcos-Contreras OA, Hood ED, Brysgel TV, Nong J, Papp TE, Eaton DM, Riley R, Palanki R, Musunuru K, Brenner JS, Mitchell MJ, Ferrari VA, Mui BL, Semple SC, Weppler SA, Atluri P, Margulies KB, Weissman D, Muzykantov VR. Systemic delivery of biotherapeutic RNA to the myocardium transiently modulates cardiac contractility in vivo. Proc Natl Acad Sci U S A. 2025 Jul 22;122(29):e2409266122. doi: 10.1073/pnas.2409266122.