Cardiomyocyte-targeted anti-inflammatory nanotherapeutics against myocardial ischemia reperfusion (IR) injury
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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.
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Cardiomyocyte-targeted anti-inflammatory nanotherapeutics against myocardial ischemia reperfusion (IR) injury
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.
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Acknowledgements
We appreciate the funding support from the National Natural Science Foundation of China (No. 52033006 and 51873142), Suzhou Science and Technology Development Project (No. SYS2019072), Collaborative Innovation Center of Suzhou Nano Science & Technology, the 111 project, Suzhou Key Laboratory of Nanotechnology and Biomedicine, and Joint International Research Laboratory of Carbon-Based Functional Materials and Devices.
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