Dual-mode immunotherapy: ultrasound responsive zinc-based nano-contract agents synergistically activate the GAS-STING pathway for enhanced tumor sono-metalloimmunotherapy

Triple-negative breast cancer has previously been considered to a weak tumor immunogenicity. A strategy combining sono-immunotherapy and metal ion interference therapy holds promise for the tumor immune environment. 2,2-azobis[2-(2-imidazolin-2-yl)propane] dihydrochloride (AIPH), functioning as a sonosensitizer, can produce alkyl radicals that can trigger sono-oxidative stress in neoplastic cells. Metal ion interference therapy has also demonstrated promise as an immunotherapy. However, the AIPH's chemical instability and the metal ions are limited by the short half-life of blood components and the lack of specificity. Herein, we developed a multifunctional nanoparticle HA/AIPH@ZIF-8 (HAZ), which incorporates hyaluronic acid (HA) specifically targeting CD44 receptors. This design aims to facilitate the targeted accumulation of nanoparticles within tumor microenvironments. HAZ amplifies sono-oxidative stress and the release of mitochondrial DNA and nuclear DNA damage. Both dsDNA and zeolitic imidazolate framework (ZIF-8) derived zinc ions (Zn²⁺) to facilitate the STING pathway and immunogenic cell death (ICD) mediated maturation of dendritic cells, infiltration of cytotoxic T lymphocytes(CTLs), the nitrogen produced by the dehydration of AIPH can increase the acoustic cavitation effect, promoting HAZ penetration at the tumor. The real-time ultrasound imaging capabilities of HAZ are also attributed to the generation of nitrogen. In general, HAZ-mediated sonodynamic therapy (SDT) might offer contrast-enhanced imaging and an efficient anticancer sono-metalloimmunotherapy.