Ultrasound‐Mediated Biomimetic Microbubbles Effectively Reverse LSECs Capillarization and Exert Antiplatelet Therapy in Liver Fibrosis

A targeted drug delivery system (Sim-MB_PLT) with a natural capacity of specifically homotypic targeting to liver sinusoidal endothelial cells (LSECs) is developed for the first time. Under ultrasound-targeted microbubble destruction (UTMD), Sim-M_BPLT bound to LSECs prevents pathogenic platelet (PLT) homing to LSECs competitively and reverses capillarization in LSECs to abrogate liver fibrosis by inhibiting the hepatic stellate cells (HSCs) activation.

Abstract

Liver fibrosis, characterized by excessive tissue remodeling as a response to chronic liver injury, is accompanied by capillarization of liver sinusoidal endothelial cells (LSECs) and activated hepatic stellate cells (HSCs). Simvastatin (Sim) can modulate endothelial function by increasing endothelial nitric oxide synthase (eNOS)-dependent nitric oxide (NO) release, thereby reversing capillarization and attenuating liver fibrosis. However, monotherapy often demonstrates limited therapeutic effectiveness given the complex pathophysiology of liver fibrosis. Herein, a type of multifunctional liposomal microbubbles (MBs) carrying both Sim and platelet membrane (PM) has been designed for drug delivery targeting the inflammatory LSECs, with ultrasound-targeted microbubble destruction (UTMD) to mediate efficient release of these therapeutic agents inside the liver sinusoidal. In rat liver fibrosis model, the multifunctional MBs reverses capillarization through the increase of eNOS-dependent NO production. Subsequently, the MBs adhering to the inflammatory LSECs block the adhesion and activation of inherent platelet (PLT), thereby decreasing platelet-derived growth factor β (PDGF-β) to inhibit the HSCs activation. This study demonstrates the strong therapeutic efficacy of the multifunctional MBs integrating Sim and PLT against liver fibrosis, which highlights a great potential for effectively managing this intractable chronic disease.