Gambogic Acid Based Coordination Polymer Reinforces High‐Intensity Focused Ultrasound Treatment of Gynecologic Malignancies

High-intensity focused ultrasound (HIFU) is emerging as a promising non-invasive treatment for solid tumors. Nevertheless, HIFU may also induce the upregulation of Heat Shock Protein 90 (HSP-90), potentially resulting in resistance to HIFU. Besides, although it is effective against in situ tumors, challenges remain with tumor metastasis and recurrence. Herein, the innovative design of gambogic acid (GA) based coordination polymer-GAZn-PEG nanoparticles (GAZn-PEG NPs) are synthesized through the coordination of GA with zinc ions (Zn²⁺), and subsequently functionalized with lipid bilayer incorporating polyethylene glycol (PEG), sensitizing HIFU for the treatment of cervical and ovarian cancers. Briefly, under HIFU exposure, GA markedly suppresses the expression of HSP-90, thereby increasing the tumor's sensitivity to HIFU therapy. Furthermore, Zn²⁺ not only overcome the issue of GA's poor water solubility but also synergistically stimulate immune responses in conjunction with GA. More intriguingly, it has been discovered that GAZn-PEG can effectively activate the cyclic GMP-AMP synthase-stimulator of the interferon genes (cGAS-STING) pathway, thereby enhancing the immune responses provoked by HIFU. Specifically, GAZn-PEG NPs show a remarkable increase in dendritic cell activation and the effective stimulation of the cGAS-STING pathway, crucial for long-term protection against tumor recurrence and metastasis.