Intrauterine Perfusion of Versatile Nanotherapeutics for Revolutionizing Sono‐Chemotherapeutic Treatment of Orthotopic Choriocarcinoma

Abstract Choriocarcinoma (CC) is a malignant solid tumor caused by abnormal differentiation of placental trophoblast cells. Clinical treatment is mainly based on systemic intravenous chemotherapy, which faces multi therapeutic challenges. In this study, we pioneered the intrauterine perfusion route to treat orthotopic choriocarcinoma and achieved a precise targeting effect combined with sonodynamic therapy (SDT). Our research meticulously developed an innovative biomimetic drug delivery system, designated as HIC@M nanoparticles (HIC@M NPs). This system involved the incorporation of cisplatin (CDDP) and indocyanine green (ICG) onto hydrazide‐modified hyaluronic acid (HHA), followed by encapsulation within a cancer cell membrane. The prepared HIC@M NPs could deplete GSH, generate large amounts of reactive oxygen species (ROS), and sensitize CDDP for higher therapeutic efficiency. In vivo results demonstrated that the collaborative application of HIC@M NPs and SDT achieved optimal therapeutic efficacy while concurrently minimizing the adverse effects. By depleting GSH and generating ROS at the tumor site, HIC@M nanoparticles not only modified the tumor microenvironment to improve the effectiveness of CDDP and mitigated drug resistance but also induced apoptosis and ferroptosis by activating the p53 signaling pathway. In conclusion, HIC@M NPs intrauterine perfusion combined with SDT culminates in a comprehensive anti‐tumor strategy for the treatment of choriocarcinoma.