CHP/MMP2 dual-targeting soft mesoporous organosilica nanoparticles loaded with losartan for modulating cardiac fibrosis

Abstract

Myocardial fibrosis (MF) drives heart failure and arrhythmias, yet drug delivery to injured myocardium is hindered by the dynamic cardiac microenvironment and lack of lesion-specific targeting. Here, we developed a dual-targeted, soft mesoporous organosilica nanoparticles (SMONs) system, which were co-functionalized with a cardiac homing peptide (CHP) and an anti-matrix metalloproteinase 2 antibody (Ab-MMP 2) for the delivery of losartan (LOS). LOS@SMONs-CHP/MMP2 exhibited excellent deformability and outstanding cellular uptake capability. In a murine model of isoproterenol (ISO)-induced myocardial fibrosis, LOS@SMONs-CHP/MMP2 exhibited significantly increased accumulation of fibrosis. In vitro treatment with these nanoparticles potently suppressed cardiac fibroblast activation, proliferation and migration, and markedly reduced collagen deposition and expression of fibrotic markers in vivo. Consequently, cardiac systolic function was substantially improved, outperforming free losartan. Comprehensive biosafety evaluations confirmed minimal cytotoxicity and no acute organ toxicity. This study offering a promising and translatable nano platform for the treatment of cardiac fibrosis.