Abstract
Myocardial ischemia-reperfusion injury (MIRI) remains a significant therapeutic challenge due to insufficient targeted drug delivery. Recognizing heme as a key endogenous signal that has yet to be utilized in delivery systems, we designed the first heme-responsive nanovesicle (DecAS-PC@NM) for lesion-specific therapy through a cascade reaction involving two functionalized phospholipids. Specifically, heme activates the artemisinin-modified phospholipid (A-PC) to generate reactive oxygen species, which oxidize the thioether structure in another phospholipid (S-PC), triggering a hydrophilic-to-hydrophobic transition and subsequent vesicle disassembly. Co-assembly with neutrophil membranes further enhances chemotaxis toward inflammatory sites. In vitro studies confirm the unique heme responsiveness of DecAS-PC@NM, while in vivo data highlight its ischemic core targeting and significant therapeutic improvement. This innovative heme-triggered phospholipid cascade offers a promising strategy for MIRI treatment.