Dual-ligand supramolecular nanofibers inspired by the renin-angiotensin system for the targeting and synergistic therapy of myocardial infarction

Abstract

<b>Rationale:</b> The compensatory activation of the renin-angiotensin system (RAS) after myocardial infarction (MI) plays a crucial role in the pathogenesis of heart failure. Most existing studies on this subject focus on mono- or dual-therapy of blocking the RAS, which exhibit limited efficacy and often causes serious adverse reactions. Few studies have been conducted on targeted therapy based on the activated RAS post-MI. Thus, the development of multiple-functional nanomedicine with concurrent targeting ability and synergistic therapeutic effect against RAS may show great promise in improving cardiac function post-MI. <b>Methods:</b> We utilized a cooperative self-assembly strategy constructing supramolecular nanofibers- telmisartan-doped co-assembly nanofibers ( <b><i>TDCNfs</i></b> ) to counter-regulate RAS through targeted delivery and combined therapy. <b><i>TDCNfs</i></b> were prepared through serial steps of solvent exchange, heating incubation, gelation, centrifugation, and lyophilization, in which the telmisartan was doped in the self-assembly process of <b><i>Ang1-7</i></b> to obtain the co-assembly nanofibers wherein they act as both therapeutic agents and target-guide agents. <b>Results: <i>TDCNfs</i></b> exhibited the desired binding affinity to the two different receptors, AT1R and MasR. Through the dual ligand-receptor interactions to mediate the coincident downstream pathways, <b><i>TDCNfs</i></b> not only displayed favorably targeted properties to hypoxic cardiomyocytes, but also exerted synergistic therapeutic effects in apoptosis reduction, inflammatory response alleviation, and fibrosis inhibition <i>in vitro</i> and <i>in vivo</i>, significantly protecting cardiac function and mitigating post-MI adverse outcomes. <b>Conclusion:</b> A dual-ligand nanoplatform was successfully developed to achieve targeted and synergistic therapy against cardiac deterioration post-MI. We envision that the integration of multiple therapeutic agents through supramolecular self-assembly would offer new insight for the systematic and targeted treatment of cardiovascular diseases.