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Previous studies have shown that tilianin alleviates ischemia-reperfusion-induced cardiomyocyte injury. However, its clinical translation has been hampered because of its insolubility in water. Tilianin-based nano-micelles that may overcome this critical issue are presented. A polyethylene glycol compound was covalently attached to propylene sulfide-formed amphiphilic diblock polymers. In the aqueous solution, tilianin is encapsulated in a hydrophobic shell to form nano-micelles. The Ph-PPS-PEG self-assembled into nanoscale micelles with a size of approximately 70 nm, termed “tilianin-loaded micelles” (TLMs). TLMs are highly efficient hydrogen peroxide scavengers and the activity of caspase-3 inhibition, thereby protecting cells from H/R-induced cytotoxicity. In addition, TLMs decreased levels of MDA, IL-1 and tumor necrosis factor (TNF-α), inhibited apoptosis, TLR4 and nuclear transcription factor (NF-κB p65) protein expression in hypoxia-reoxygenation (H/R) model. Taken together, the study suggests that TLMs may be of clinical value for the protective effects of cardiomyocytes by inhibiting Inflammation and oxidative stress during myocardial ischemia-reperfusion injury.