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

• 成果类型: Article
• 署名作者: V. Shuvaev, Vladimir; Tam, Ying K.; Lee, Benjamin W.; Myerson, Jacob W.; Herbst, Alan; Kiseleva, Raisa Yu.; Glassman, Patrick M.; Parhiz, Hamideh; Alameh, Mohamad-Gabriel; Pardi, Norbert; Muramatsu, Hiromi; Shuvaeva, Tea I.; Arguiri, Evguenia; Marcos-Contreras, Oscar A.; Hood, Elizabeth D.; V. Brysgel, Taylor; Nong, Jia; Papp, Tyler E.; Eaton, Deborah M.; Riley, Rachel; Palanki, Rohan; Musunuru, Kiran; Brenner, Jacob S.; Mitchell, Michael J.; Ferrari, Victor A.; Mui, Barbara L.; Semple, Sean C.; Weppler, Sherry A.; Atluri, Pavan; Margulies, Kenneth B.; Weissman, Drew; Muzykantov, Vladimir R.
• 署名单位: University of Pennsylvania; University of Pennsylvania; University of Pennsylvania; Pennsylvania Commonwealth System of Higher Education (PCSHE); Temple University; University of Pennsylvania; University of Pennsylvania; University of Pennsylvania; University of Pennsylvania; Rowan University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9865
• DOI: 10.1073/pnas.2409266122
• 发表日期: 2025-07-22
• 关键词: drug-delivery; heart-failure; extracellular vesicles; gene-therapy; nanoparticles; expression

摘要

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.