Biomimetic Nanotherapy Targeting lncRNA TUG1 Alleviates Doxorubicin-Induced Cardiomyopathy by Suppressing...

Doxorubicin (DOX)-induced cardiomyopathy remains therapeutically challenging due to the absence of pathway-specific interventions. Ferroptosis of cardiac microvascular endothelial cells (CMECs) is a major driver of disease progression, yet precise therapeutic strategies remain limited. Here, mechanistic analyses identified lncRNA TUG1 as an upstream promoter of CMEC ferroptosis through the miR-153-5p/MMP2-TIMP2/TFR-1 axis. Guided by this mechanism, a translational construct was developed by cloaking mesoporous silica nanoparticles carrying TUG1-targeting siRNA with neutrophil membranes (NM@si-TUG1/MSN). The neutrophil membrane coating enabled robust cardiac tropism and preferential CMEC uptake. In a murine model of DOX-induced cardiomyopathy, NM@si-TUG1/MSN accumulated in the heart, achieved effective TUG1 knockdown, and markedly reduced ferroptosis. Relative to free siRNA and uncoated nanoparticles, the nanocomplex produced superior outcomes, including restoration of microvascular integrity, reduced fibrosis, and significant improvement in cardiac function. This study characterizes a regulatory axis in DOX-induced cardiomyopathy and demonstrates a targeted biomimetic nanotherapy that interrupts microvascular ferroptosis and limits disease progression. The data support the feasibility of this approach for clinical translation.