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Research Article

Cardiomyocyte-targeted anti-inflammatory nanotherapeutics against myocardial ischemia reperfusion (IR) injury

Min Lan1, Mengying Hou1, Jing Yan1( ), Qiurong Deng1, Ziyin Zhao1, Shixian Lv1, Juanjuan Dang1, Mengyuan Yin1, Yong Ji2( ), Lichen Yin1( )
Institute of Functional Nano and Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou 215123, China
Department of Cardiothoracic Surgery, Wuxi People’s Hospital Affiliated to Nanjing Medical University, Wuxi 214023, China
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Graphical Abstract

Cardiomyocyte-targeting and reactive oxygen species (ROS)-ultrasensitive nanocomplexes (NCs) based on mesoporous silica nanoparticles gated with a ROS-degradable polycation (PPTP) were prepared for the co-delivery of siRAGE and Dex toward the anti-inflammatory treatment against myocardial ischemia reperfusion (IR) injury. The NCs efficiently entered cardiomyocytes, and PPTP was sensitively degraded by the over-produced ROS, releasing the siRAGE and Dex to mediate RAGE silencing and cooperative anti-inflammatory effect.

Abstract

Myocardial ischemia reperfusion (IR) injury is closely related to the overwhelming inflammation in the myocardium. Herein, cardiomyocyte-targeted nanotherapeutics were developed for the reactive oxygen species (ROS)-ultrasensitive co-delivery of dexamethasone (Dex) and RAGE small interfering RNA (siRAGE) to attenuate myocardial inflammation. PPTP, a ROS-degradable polycation based on PGE2-modified, PEGylated, ditellurium-crosslinked polyethylenimine (PEI) was developed to surface-decorate the Dex-encapsulated mesoporous silica nanoparticles (MSNs), which simultaneously condensed siRAGE and gated the MSNs to prevent the Dex pre-leakage. Upon intravenous injection to IR-injured rats, the nanotherapeutics could be efficiently transported into the inflamed cardiomyocytes via PGE2-assisted recognition of over-expressed E-series of prostaglandin (EP) receptors on the cell membranes. Intracellularly, the over-produced ROS degraded PPTP into small segments, promoting the release of siRAGE and Dex to mediate effective RAGE silencing (72%) and cooperative anti-inflammatory effect. As a consequence, the nanotherapeutics notably suppressed the myocardial fibrosis and apoptosis, ultimately recovering the systolic function. Therefore, the current nanotherapeutics represent an effective example for the co-delivery and on-demand release of nucleic acid and chemodrug payloads, and might find promising utilities toward the synergistic management of myocardial inflammation.

Keywords

small interfering RNA (siRNA) deliveryreactive oxygen species (ROS) responsivenessditellurium-crosslinked polyethylenimine (PEI)myocardial ischemia reperfusion injuryanti-inflammation

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Nano Research
Volume 15 Issue 10,
October 2022
Pages 9125-9134
DOI: 10.1007/s12274-022-4553-6
Cite this article:
Lan M, Hou M, Yan J, et al. Cardiomyocyte-targeted anti-inflammatory nanotherapeutics against myocardial ischemia reperfusion (IR) injury. Nano Research, 2022, 15(10): 9125-9134. https://doi.org/10.1007/s12274-022-4553-6
Topics:
RNATargeted drug delivery

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Received: 07 April 2022
Revised: 11 May 2022
Accepted: 16 May 2022
Published: 27 July 2022
© Tsinghua University Press 2022
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