Bridging acute-chronic myocardial infarction treatment: Dual-regulating of ROS/fibrosis via microenvironment-responsive release of NO and curcumin

Oxidative stress and fibrosis are core drivers of post-myocardial infarction dysfunction. Conventional therapies predominantly address either acute oxidative damage or chronic fibrosis, lacking strategies that concurrently target the two interconnected processes. Here, a microenvironment-responsive nanomedicine delivering nitric oxide (NO) and curcumin specifically to the infarcted heart is presented (named C@Si-NM). Constructed from glutathione-sensitive cyclic nitrate-trimethylene carbonate-polyethylene glycol block copolymer micelles crosslinked with silica, the system releases both NO and the encapsulated curcumin upon encountering elevated glutathione levels at the infarction site. In cardiomyocytes, NO suppresses the opening of mitochondrial permeability transition pore, inhibiting the release of reactive oxygen species, while curcumin directly acts as an antioxidant. In fibroblasts, NO inhibits the TGF-β/Smad pathway and curcumin downregulates the production of TGF-β, jointly suppressing fibrosis. The combined nanomedicine C@Si-NM significantly improved cardiac function in a rat model of MI after four weeks of treatment, resulting in an ejection fraction of 74 %. This value approached the normal range of 81 % and was superior to the outcomes observed with NO monotherapy at 62 % or curcumin monotherapy at 63 %. This strategy effectively mitigates both oxidative damage and fibrosis, bridging the gap between acute and chronic therapeutic interventions of myocardial infarction.