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<p>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.</p> Graphical abstract <p></p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月26日

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  • Hao Jin,
  • Jiandong Ding,
  • Xiaoguo Zhang,
  • Shouquan Cheng,
  • Yahao Zhang,
  • Yong Wu,
  • Cihui Liu,
  • Sirui Yang,
  • Anjian Zhang,
  • Genshan Ma,
  • Wenbin Lu

摘要

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