Targeted delivery of TAPI-1 via biomimetic nanoparticles ameliorates post-infarct left ventricle function and remodeling.

Abstract

Aims: The potential of nanoparticles as effective drug delivery tools for treating failing hearts in heart failure remains a challenge. Leveraging the rapid infiltration of neutrophils into infarcted hearts after myocardial infarction (MI), we developed a nanoparticle platform engineered with neutrophil-membrane proteins for the targeted delivery of TAPI-1, a TACE/ADAM17 inhibitor, to the inflamed myocardium, aiming to treat cardiac dysfunction and remodeling in rats with MI.

Methods and results: Neutrophil-mimic liposomal nanoparticles (Neu-LNPs) were constructed by integrating synthesized liposomal nanoparticles with LPS-stimulated neutrophil membrane fragments and then loaded with TAPI-1. MI rats were treated with TAPI-1 delivered via Neu-LNPs for 4 weeks. Left ventricular function was assessed by echocardiography and cardiac fibrosis was evaluated post-treatment. The novel Neu-LNPs maintained typical nanoparticle features, but with increased biocompatibility. Neu-LNPs demonstrated improved targeting ability and cellular internalization, facilitated by LFA1/Mac1/ICAM-1 interaction. Neu-LNPs displayed higher accumulation and cellular uptake by macrophages and cardiomyocytes in infarcted hearts post-MI, with a sustained duration. Treatments with TAPI-1-Neu-LNPs demonstrated greater protection against myocardial injury and cardiac dysfunction in MI rats compared to untargeted TAPI-1, along with reduced cardiac collagen deposition and expression of fibrosis biomarkers as well as altered immune cell compositions within the hearts.

Conclusions: Targeted treatment with TACE/ADAM17 inhibitor delivered via biomimetic nanoparticles exhibited pronounced advantages in improving left ventricle function, mitigating cardiac remodeling, and reducing inflammatory responses within the infarcted hearts. This study underscores the effectiveness of Neu-LNPs as a drug delivery strategy to enhance therapeutic efficacy in clinical settings.