Improved cardiac-specific delivery of RAGE siRNA within small extracellular vesicles engineered to express intense cardiac targeting peptide attenuates myocarditis

Hyoeun Kim, Dasom Mun, Ji Young Kang, Seung Hyun Lee, Nuri Yun, Boyoung Joung

Research output: Contribution to journalArticlepeer-review

Abstract

Small extracellular vesicles (sEVs) are nanometer-sized membranous vesicles secreted by cells, with important roles in physiological and pathological processes. Recent research has established the application of sEVs as therapeutic vehicles in various conditions, including heart disease. However, the high risk of off-target effects is a major barrier for their introduction into the clinic. This study evaluated the use of modified sEVs expressing high levels of cardiac-targeting peptide (CTP) for therapeutic small interfering RNA (siRNA) delivery in myocarditis, an inflammatory disease of heart. sEVs were extracted from the cell culture medium of HEK293 cells stably expressing CTP-LAMP2b (referred to as C-sEVs). The cardiac targeting ability of C-sEVs with the highest CTP-LAMP2b expression was >2-fold greater than that of normal sEVs (N-sEVs). An siRNA targeting the receptor for advanced glycation end products (RAGE) (siRAGE) was selected as a therapeutic siRNA and loaded into C-sEVs. The efficiency of cardiac-specific siRNA delivery via C-sEVs was >2-fold higher than that via N-sEVs. Furthermore, siRAGE-loaded C-sEVs attenuated inflammation in both cell culture and an in vivo model of myocarditis. Taken together, C-sEVs may be a useful drug delivery vehicle for the treatment of heart disease.

Original languageEnglish
Pages (from-to)1024-1032
Number of pages9
JournalMolecular Therapy - Nucleic Acids
Volume24
DOIs
Publication statusPublished - 2021 Jun 4

Bibliographical note

Funding Information:
This study was supported by research grants from the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology ( NRF-2017R1A2B3003303 ) and from the Korean Healthcare Technology R&D Project funded by the Ministry of Health & Welfare ( HI16C0058 ), as well as by a CMB-Yuhan research grant from Yonsei University College of Medicine for 2019 ( 6-2019-0124 ). The authors thank Medical Illustration & Design, part of the Medical Research Support Services of Yonsei University College of Medicine, for all artistic support related to this work.

Publisher Copyright:
© 2021 The Author(s)

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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