X‐Ray Triggered Phase SHIFT in Radiosensitizer‐Lipiodol Formulation for Controlled Synergistic TAE−XDT Cancer Therapy

Abstract The integration of local radiation therapy (RT) with transcatheter arterial chemoembolization (TACE) can effectively manage unresectable hepatocellular carcinoma (HCC). Nonetheless, achieving effective synergistic treatment efficacy by controlled on‐dem, radiosensitization following TACE remains a significant issue. A nanoradiosensitizer‐Lipiodol formulation (DSeSeP‐API(Lip)) is developed using Touch‐, ‐Go following X‐ray irradiation (X‐tag) for the theranostics of HCC. The nanoradiosensitizer (DSeSeP‐API) is fabricated by conjugating ultrasmall AuPtICG (API) nanoparticles featuring an amphiphilic polymer with X‐ray responsive diselenide motif (DSPE‐Se‐Se‐PEG‐SH), satisfying the ‘3 s ’ properties: 1) s table in Lipiodol; 2) s ensitive to X‐ray; 3) phase‐ s hift from Lipiodol to the aqueous physiology. The homogeneous, stable lipiodol formulation is subsequently prepared via our super‐stable homogeneous intermixed formulation technology (SHIFT). Following the successful transcatheter arterial embolization (TAE), the subsequent RT program commences. The initial X‐ray irradiation is administered concurrently with the cleavage of the diselenide bond to facilitate the phase transition of hydrophilic SeP‐API from Lipiodol ( 1 X‐Tag). Secondary X‐ray irradiation is applied at the peak cellular uptake of sensitizers for enhanced X‐ray dynamic therapy (XDT) ( 2 X‐ray). The research illustrates the capability of the nanoradiosensitizer‐Lipiodol formulation with the “X‐tag” feature to amplify the synergistic TAE−XDT therapeutic effects while effectively minimizing adverse effects.