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.