Thyroid‐Targeted Nano‐Bombs Empower HIFU for Graves' Disease

Abstract Graves' disease (GD) is an autoimmune disorder with a high incidence rate, particularly affecting women of reproductive age. Current treatment modalities for GD carry significant disadvantages, especially for pregnant or nursing women. As a novel extracorporeal therapeutic technique, high‐intensity focused ultrasound (HIFU) shows great promise for treating GD; however, its low treatment efficacy impedes clinical application. In this study, a thyroid‐targeted nano‐bomb system (PD‐PLGA@Si‐Ab/PDA‐I, PSAPI) is developed to enhance HIFU efficacy and improve therapeutic outcomes for GD. The core structure of PSAPI encapsulates a phase‐transition material, perfluorohexane, and the anti‐inflammatory drug diclofenac within a poly(lactide‐co‐glycolide) (PLGA) and silica shell. A polydopamine coating enhances biocompatibility, while iodine loading and thyroid‐stimulating hormone receptor (TSHR) antibodies grafting ensure targeted delivery to the thyroid. Robust in vitro and in vivo results demonstrated that PSAPI is highly biocompatible, accumulates in the thyroid within 24 h after administration, and significantly potentiates the therapeutic efficacy of HIFU, resulting in markedly reduced inflammatory responses. Transcriptomic analysis revealed a cellular defense mechanism activated in PSAPI‐treated cells following HIFU irradiation, highlighting potential molecular targets for the future development of HIFU‐sensitizing agents. The biocompatible PSAPI nano‐bomb developed in this study holds great transformative potential, addressing critical gaps in current therapeutic practices for GD.