Myocardial ischaemia/reperfusion (MI/R) injury causes adverse cardiac remodelling by activating the local renin-angiotensin system (RAS). In this study, we engineered a neutrophil membrane-biomimetic nanocarrier that facilitates the reactive oxygen species (ROS)-responsive release of valsartan (NRLP-Val) to precisely target MI/R injury. This design leverages neutrophil-derived adhesion molecules for targeted delivery to the inflamed myocardium and promotes ROS-triggered drug release at the infarct site. NRLP-Val effectively traversed activated endothelium and protected cardiomyocytes from angiotensin II-induced mitochondrial dysfunction and apoptosis in vitro. In vivo, NRLP-Val demonstrated superior cardiac accumulation and a dose-dependent therapeutic profile in a murine MI/R model. Notably, the 8 mg/kg dose achieved maximal efficacy, which was statistically equivalent to that of the 12 mg/kg dose, in acutely reducing the infarct size, oxidative stress, apoptosis, and inflammation. Long-term treatment with 8 mg/kg NRLP-Val significantly inhibited fibrosis, improved ventricular remodelling, and restored cardiac function at 28 days, outperforming the non-targeted controls and free valsartan. The platform exhibited an excellent safety profile. Therefore, 8 mg/kg NRLP-Val is a promising and clinically translatable strategy for achieving potent local RAS inhibition without systemic compromise, offering a novel targeted therapeutic approach for ischaemic heart disease.

Activation of the local renin–angiotensin system (RAS) promotes cardiomyocyte apoptosis and cardiac remodeling after acute myocardial infarction (AMI). As an anti-RAS drug, the effect of Valsartan in the early stage of acute MI is limited by its low drug concentration in the heart and low dosage. Here, by exploiting the inherent nature of neutrophils migrating to the injured myocardium and the local low-pH microenvironment caused by ischemia and hypoxia after myocardial infarction, we designed nanocarrier (NSLP)-hybridized neutrophil membranes and pH-sensitive liposomes (SLPs) for the delivery of Valsartan (NSLP-Val). These functional nanocarriers could mimic neutrophils and are homed to the injured heart; they were also found to respond to a low-pH microenvironment. In the mouse model of MI, we found that NSLP-Val could target the infarct marginal zone and release Valsartan locally in the low-pH microenvironment without affecting hemodynamic stability. Further, locally released angiotensin receptor inhibitors reduced the infarct size and inflammatory response by inhibiting cardiomyocytes. Ultimately, NSLP-Val improved cardiac function and inhibited cardiac hypertrophy and fibrosis.