Ultrasound-Triggered Nanobubbles for Endothelial-Targeted Drug Delivery in the Detection and Treatment of Doxorubicin-Induced Cardiotoxicity

Cardiotoxicity is a potential side effect of doxorubicin (DOX). However, there is a lack of effective methods for the timely detection and precise treatment of DOX-induced cardiotoxicity (DIC). Here, snRNA-seq of the hearts of patients with DIC and bulk RNA-seq of DOX-treated mice are conducted to reveal the role of endothelial dysfunction involving cell adhesion. Although previous researches have demonstrated the protective effect of dapagliflozin (DAPA) against endothelial cell (EC) injury in DIC, the low selectivity and poor accumulation greatly compromise their therapeutic efficacy. Based on these, a nanobubbles-based DAPA nanodelivery strategy (DA/VTP-NBs) containing a peptide targeting VCAM1, a highly expressed adhesion molecule in damaged EC, is then developed to improve DIC diagnosis and treatment. The DA/VTP-NBs selectively recognize damaged EC in the cardiac tissues of patients with DIC and achieve pre-functional molecular imaging. Under US-triggered controlled release, DA/VTP-NBs exhibit better therapeutic effects against DIC than free DAPA by amplifying the antioxidative, antiapoptotic, and proangiogenic effects. Mechanically, this therapeutic effect is attributed to the inhibition of mtDNA-cGAS-STING axis. The proposed DA/VTP-NBs system presents an effective strategy for timely detection and accurate treatment of DIC, providing potential clinical benefits for DIC patients.