Super‐Stable Homogeneously Sustained‐Release System Mediates Transcatheter Arterial Ionic‐Embolization Strategy for Hepatocellular Carcinoma Therapy

Abstract The clinical effectiveness of locoregional therapies in treating hepatocellular carcinoma (HCC) is frequently constrained by multi‐drug resistance and/or tumor metastasis. To surmount these challenges, a promising approach, transcatheter arterial ionic‐embolization (TAIE) is proposed, which can specifically and continuously disrupt the intracellular ionic balance to significantly inhibit tumor activity and invasion. The hydrophilic micro‐nanoscale sodium chloride particles (SCPs) are ingeniously intermixed with hydrophobic lipiodol to create a super‐stable homogeneous embolic formulation (lipiodol‐sodium chloride, LSC). After interventional administration, the LSC selectively deposits in HCC lesions, where lipiodol stably delivers SCPs to disrupt the cell's ionic balance, causing cell death without drug resistance. Notably, it is demonstrated that LSC can significantly hinder tumor cell migration and invasion. The mechanism is through SCP disruption of the ionic balance, which induces cell swelling and subsequent vimentin hydrolysis‐mediated cytoskeletal remodeling. In addition, it is found that LSC treatment notably downregulates the expression of MYLK, TLN, and THBS2 genes in the focal adhesion (FA) signaling pathway of HepG2 cells. LSC formulation integrated tumor‐specific deposition, intratumoral sustained release, efficient tumoricidal activity, significant metastasis inhibition, and excellent biological safety, thereby demonstrating superior in vivo tumor therapeutic effects via TAIE strategy, and showing a promising cancer therapeutic approach for clinical application.