Peptide-functionalized periodic mesoporous silica nanoparticles for monocyte-specific TET3 Silencing enhance cardiac repair after acute myocardial infarction

Abstract Modulating the balance between pro- and anti-inflammatory monocyte subsets holds therapeutic promise in acute myocardial infarction (AMI); however, effective and selective strategies are still lacking. In this study, we are the first to identify Ten-Eleven-Translocation 3 (TET3) expression in circulating monocytes as an independent predictor of AMI occurrence and patient prognosis in a clinical cohort. Building on this novel insight, we engineered a monocyte-targeted RNAi delivery system designed to silence TET3 expression selectively. The platform employs periodic mesoporous silica nanoparticles (PMS) loaded with siTET3, and is surface-modified with polyethylenimine (PEI) and polyethylene glycol (PEG) to enhance cellular uptake. Critically, we further functionalized the system with a CD14 receptor-recognizing transmembrane peptide (Cys-Gly-Trp-Arg-Arg-Arg-NH₂), enabling precise monocyte targeting and internalization. Our targeted nanotherapeutic successfully reprogrammed inflammatory monocytes in vitro, leading to attenuated pro-inflammatory phenotypes. In vivo, treatment with siTET3-loaded nanoparticles markedly reduced infarct size and myocardial fibrosis in murine AMI models. Importantly, translational validation in a porcine AMI model demonstrated substantial suppression of cardiac inflammation and improved post-infarction outcomes following systemic administration of the nanotherapeutic. Graphical abstract