Interferon-stimulated gene 15 small interfering RNA-loaded polarized mesoporous silica nanocarriers remodel the immune microenvironment to ameliorate post-myocardial infarction heart failure.

This study developed polarized mesoporous silica nanocarriers (pMSNCs) loaded with interferon-stimulated gene 15 (ISG15) small interfering RNA (siRNA) to modulate inflammation and immune cell activation in the cardiac microenvironment post-myocardial infarction (MI) and to evaluate their therapeutic efficacy in heart failure (HF). Single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq analyses in mouse and rat models identified key cell clusters, differentially expressed genes (DEGs), and prognostically relevant hub genes, including ISG15. The synthesized pMSNC@ISG15 siRNA nanoparticles effectively suppressed ISG15 expression in cardiac cells, exhibited excellent biocompatibility, and inhibited immune cell activation in vivo. In the post-MI HF rat model, treatment with pMSNC@ISG15 siRNA led to significant improvements in cardiac function, reduced fibrosis, and increased M2-type macrophages, highlighting its potential as a nanomedicine-based therapeutic strategy for HF. The study provides valuable insights into the use of nanocarriers for targeted gene therapy in cardiac diseases.