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. 2025 Jul 22;122(29):e2409266122.
doi: 10.1073/pnas.2409266122. Epub 2025 Jul 16.

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

Vladimir V Shuvaev  1 , Ying K Tam  2 , Benjamin W Lee  3 , Jacob W Myerson  1 , Alan Herbst  4 , Raisa Yu Kiseleva  1 , Patrick M Glassman  1   5 , Hamideh Parhiz  1   6 , Mohamad-Gabriel Alameh  6 , Norbert Pardi  6 , Hiromi Muramatsu  6 , Tea I Shuvaeva  1 , Evguenia Arguiri  1 , Oscar A Marcos-Contreras  1 , Elizabeth D Hood  1 , Taylor V Brysgel  1 , Jia Nong  1 , Tyler E Papp  6 , Deborah M Eaton  3 , Rachel Riley  7 , Rohan Palanki  7 , Kiran Musunuru  3 , Jacob S Brenner  8 , Michael J Mitchell  7 , Victor A Ferrari  3 , Barbara L Mui  2 , Sean C Semple  2 , Sherry A Weppler  2 , Pavan Atluri  4 , Kenneth B Margulies  3 , Drew Weissman  6 , Vladimir R Muzykantov  1
Affiliations

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

Vladimir V Shuvaev et al. Proc Natl Acad Sci U S A. .

Abstract

Lipid nanoparticles (LNP) represent a versatile platform for improving delivery of therapeutic nucleic acids. Yet, delivery to the myocardium remains a formidable challenge due to local barriers in the heart and systemic hindrances. In particular, plasma apolipoprotein E (apoE) directs LNP to the liver, limiting potential extrahepatic delivery. Here, we report a cardiotropic LNP (cLNP), which within 30 min post-intravenous injection accumulates in the heart of ApoE knockout (Apoe-/-) mice. The findings were confirmed for Apoe-/- rats and for wild-type mice after siRNA-mediated plasma apoE ablation. To test cardiac-specific functional effects as a proof of concept, we used cLNP loaded with siRNA to ATP2A2, encoding the sarcoplasmic-endoplasmic reticulum Ca2+ ATPase 2a (SERCA2A). This cardiomyocyte-specific protein is a key regulator of contractility and relaxation. Intravenous administration of cLNP/siRNA-ATP2A2 in Apoe-/-mice led to near-complete ablation of SERCA2A in the myocardium and a potent modulation of contractility of the cardiomyocytes obtained from these mice. In summary, cardiotropic nanocarriers may allow the delivery and effect of RNA and other agents to the myocardium. Achieving this unmet medical need promises new types of treatment for heart diseases, which remains the leading cause of death worldwide.

Keywords: SERCA2; cardiac drug delivery; lipid nanoparticles; mRNA; siRNA.

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Conflict of interest statement

Competing interests statement:Y.K.T., B.L.M, S.C.S. and S.A.W. are employees of Acuitas Therapeutics., Y.K.T. and B.L.M. hold equity in Acuitas Therapeutics., D.W., V.R.M., and V.V.S. have filed a patent application based on some aspects of this work.

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