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

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 ROSdegradable 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 antiinflammatory 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 codelivery and on-demand release of nucleic acid and chemodrug payloads,and might find promising utilities toward the synergistic management of myocardial inflammation.