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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

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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
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