Engineering a Sonotherapeutic RBC Membrane‐Derived Nanoparticle Platform for the Treatment of Liver Cancer

ABSTRACT Hepatocellular carcinoma (HCC), a type of liver cancer, is a leading cause of cancer‐related death worldwide. Current therapies vary depending on the severity of cancer and include treatment strategies such as surgical resection, liver transplantation, radiotherapy, and chemoembolization. However, these treatment strategies are limited due to their invasive nature, lack of organ donors, and potential toxic side effects. As an alternative, sonotherapy (ST) has emerged as a promising non‐invasive approach. ST uses ultrasound to activate sonosensitizers such as indocyanine green (ICG), inducing high levels of ROS and leading to cancer cell death. Nonetheless, ICG's clinical use is currently hampered by its aqueous instability, short half‐life, and rapid clearance from the body. In this paper, we enhanced ICG's potential by developing an ICG‐loaded RBC‐based cell membrane‐derived nanoparticle (CMN‐ICG). Our designed CMN‐ICG demonstrated excellent cytocompatibility and enhanced uptake by HepG2 cells. Further, the ultrasound‐mediated anticancer performance of CMN‐ICG is evaluated in vitro in both 2D and 3D cancer cell environments. Under ultrasound exposure, ROS production increased 2.62‐fold compared with the CMN‐ICG group without ultrasound, resulting in significant cell death and confirming the sonotherapeutic effectiveness of CMN‐ICG. Overall, the designed bio‐based CMN‐ICG shows promise as a clinically relevant sonotherapeutic platform for treating HCC.