Extradomain B fibronectin-targeted small interfering RNA-loaded biosynthetic gas vesicles for ultrasound-imaging-guided vulnerable plaque treatment.

The up-regulation of Extradomain B fibronectin (EDB-FN) levels in the extracellular matrix is a potential biomarker of advanced atherosclerotic lesions. Currently, no ultrasound molecular imaging probe targeting EDB-FN is available for EDB-FN the identification and treatment of atherosclerotic vulnerable plaques. Herein, we developed a biosynthetic gas vesicles (GVs)-based acoustic probe targeting EDB-FN, which delivered small interfering RNA (siRNA) molecules to inhibit the progression of vulnerable plaques, enabling integrated diagnosis and therapy via ultrasound. The cyclic nonapeptide CTVRTSADC (ZD2)-GVs showed highly enhanced vascular walls, while lumens were nearly not enhanced, which is different from that of traditional microbubble ultrasonic imaging in large and medium vessels. This special imaging feature facilitated the ultrasound-based detection of vulnerable plaques. The pathological analysis results showed that the synthesised integrated diagnostic and therapeutic probe EDBsiRNA@ZD2-GVs provided significant therapeutic benefits in the treatment of vulnerable plaques such as reduced lipid contents and neovascularisation, and increased collagen deposition and smooth muscle cell proliferation accompanied by downregulating expression of EDB-FN when combined with acoustic irradiation. This study demonstrated that EDBsiRNA@ZD2-GVs achieved effective ultrasound targeting visualization and delivery of siRNA to vulnerable plaques. Thus, EDBsiRNA@ZD2-GVs can be used as an ultrasound probe for the detection and therapy of vulnerable plaques.