Adaptive enzyme-responsive self-assembling multivalent apelin ligands for targeted myocardial infarction therapy

Microvascular dysfunction following myocardial infarction exacerbates coronary flow obstruction and impairs the preservation of ventricular function. The apelinergic system, known for its pleiotropic effects on improving vascular function and repairing ischemic myocardium, has emerged as a promising therapeutic target for myocardial infarction. Despite its potential, the natural apelin peptide has an extremely short circulating half-life. Current apelin analogs have limited receptor binding efficacy and poor targeting, which restricts their clinical applications. In this study, we utilized an enzyme-responsive peptide self-assembly technique to develop an enzyme-responsive small molecule peptide that adapts to the expression levels of matrix metalloproteinases in myocardial infarction lesions. This peptide is engineered to respond to the high concentration of matrix metalloproteinases in the lesion area, allowing for precise and abundant presentation of the apelin motif. The changes in hydrophobicity allow the apelin motif to self-assemble into a supramolecular multivalent peptide ligand-SAMP. This self-assembly behavior not only prolongs the residence time of apelin in the myocardial infarction lesion but also enhances the receptor-ligand interaction through increased receptor binding affinity due to multivalency. Studies have demonstrated that SAMP significantly promotes angiogenesis after ischemia, reduces cardiomyocyte apoptosis, and improves cardiac function. This novel therapeutic strategy offers a new approach to restoring coronary microvascular function and improving damaged myocardium after myocardial infarction. [Display omitted] •An MMP-induced self-assembling Apelin ligand (SAMP) was developed for myocardial infarction (MI) therapy.•SAMP self-adaptively assembles in situ into stable, high-affinity Apelin-based nanofibers in the MI microenvironment.•SAMP multivalently activates AplnR, promotes angiogenesis, inhibits cardiomyocyte apoptosis, and improves cardiac function.SAMP multivalently activates AplnR, promotes angiogenesis, inhibits cardiomyocyte apoptosis, and improves cardiac function.