Journal article
Self-assisted membrane-penetrating helical polypeptides mediate anti-inflammatory RNAi against myocardial ischemic reperfusion (IR) injury
Soochow University1
University of Groningen2
Nanjing Medical University3
Department of Health Technology, Technical University of Denmark4
Immunobiology and Biomimetics, Department of Health Technology, Technical University of Denmark5
Polymer Cell, Immunobiology and Biomimetics, Department of Health Technology, Technical University of Denmark6
Anti-inflammatory RNA interference (RNAi) provides a promising paradigm for the treatment of myocardial ischemia reperfusion (IR) injury. To overcome the membrane barriers against intracardial siRNA delivery, various guanidinated helical polypeptides with potent and aromaticity-assisted membrane activities were herein developed and used for the delivery of siRNA against RAGE (siRAGE), a critical regulator of the pro-inflammatory cascade.
Aromatic modification of the polypeptide led to notably enhanced trans-membrane siRNA delivery efficiencies, and more importantly, allowed more siRNA cargoes to get internalized via non-endocytosis, an effective pathway toward gene transfection. Subsequently, benzyl-modified polypeptide (P-Ben) was identified as the top-performing material with the highest RAGE silencing efficiency yet lowest cytotoxicity in H9C2 cells.
Intracardial injection of the P-Ben/siRAGE polyplexes at 150 μg siRNA per kg led to remarkable RAGE knockdown by ∼85%, thereby attenuating the inflammatory cytokine release and reducing the cardiomyocyte apoptosis as well as myocardium fibrosis to recover the cardiac function after IR injury. This study therefore provides an effective strategy for the design of membrane-penetrating gene delivery materials, and may provide a promising addition to the anti-inflammatory treatment of myocardial IR injury.
Language: | English |
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Year: | 2019 |
Pages: | 3717-3728 |
ISSN: | 20474849 and 20474830 |
Types: | Journal article |
DOI: | 10.1039/c9bm00719a |
ORCIDs: | 0000-0003-1738-7857 and 0000-0002-4573-0555 |