Neutrophil-like cell membrane-coated siRNA of lncRNA AABR07017145.1 therapy for cardiac hypertrophy via inhibiting ferroptosis of CMECs

Abstract

Cardiac microvascular dysfunction is associated with cardiac hypertrophy and can eventually lead to heart failure. Dysregulation of long non-coding RNAs (lncRNAs) has recently been recognized as one of the key mechanisms involved in cardiac hypertrophy. However, the potential roles and underlying mechanisms of lncRNAs in cardiac microvascular dysfunction have not been explicitly delineated. Our results confirmed that cardiac microvascular dysfunction was related to cardiac hypertrophy and ferroptosis of cardiac microvascular endothelial cells (CMECs) occurred during cardiac hypertrophy. Using a combination of in vivo and in vitro studies, we identified a lncRNA AABR07017145.1, named as lncRNA AAB for short, and revealed that lncRNA AAB was upregulated in the hearts of cardiac hypertrophy rats as well as in the Ang II-induced CMECs. Importantly, we found that lncRNA AAB sponged and sequestered miR-30b-5p to induce the imbalance of MMP9/ TIMP1, which enhanced the activation of transferrin receptor 1 ( TFR-1) and then eventually led to the ferroptosis of CMECs. Moreover, we have developed a delivery system based on neutrophil membrane (NM)-camouflaged mesoporous silica nanocomplex (MSN) for inhibition of cardiac hypertrophy, indicating the potential role of silenced lncRNA AAB (si- AAB) and overexpressed miR-30b-5p as the novel therapy for cardiac hypertrophy.

Graphical abstract

Neutrophil membrane-camouflaged core-shell structure for siRNA of lncRNA AAB inhibits CMEC ferroptosis in cardiac hypertrophy rat NM + si- AAB + MSN targets injured CMECs. Upon the uptake by CMECs, NM + si- AAB + MSN is decomposed and releases siRNA into cytoplasm. si- AAB increases miR-30b-5p, and then miR-30b-5p regulates the MMP9/ TIMP1 balance, which leads to suppression of the activation of TFR-1 to reduce iron toxicity, and ultimately inhibits CMEC ferroptosis.

Abstract

lncRNA AAB sponged and sequestered miR-30b-5p to induce the imbalance of MMP9/ TIMP1, which enhanced the activation of TFR-1 and then eventually led to the ferroptosis of CMECs in cardiac hypertrophy. We have developed a nanocomplex that can be targeted to delivery si- AAB or miR-30b-5p to injured CMECs, which inhibits CMEC ferroptosis.