Zinc Coordination Lipid Nanoparticles Co‐Delivering Calcium Peroxide and Chelating STING agonist for Enhanced Cancer Metalloimmunotherapy

Metalloimmunotherapy has achieved great preclinical success against malignant tumors. Nonetheless, the limited immune cell infiltration and impaired immunogenicity within the tumor microenvironment (TME) significantly hinder its translation to clinical applications. In this study, a zinc coordination lipid nanoparticle is developed loaded with calcium peroxide hydrate (CaO2) nanoparticles and the STING agonist diABZI‐2, which is termed A‐CaO2‐Zn‐LNP. The release of Zn2+ from the A‐CaO2‐Zn‐LNP and the calcium overload synergistically induced immunogenic cell death (ICD). In addition, CaO2 nanoparticles can consume H+ and release oxygen (O2) under acidic conditions. This treatment increased the pH and alleviated the hypoxia of the TME. Along with cGAS‐STING activation by diABZI‐2, A‐CaO2‐Zn‐LNP ultimately results in enhanced anti‐tumor systemic immunity and long‐term immune memory via alleviating the immunosuppressive microenvironment. Taken together, A‐CaO2‐Zn‐LNP offers a new nanoplatform that expands its application for cancer treatment by metalloimmunotheray. This work developed a nanovaccine platform termed A‐CaO2‐Zn‐LNP, which is a zinc coordination lipid nanoparticle loaded with calcium peroxide hydrate (CaO2) nanoparticles and the STING agonist diABZI‐2. The nanoparticle system is demonstrated to trigger intracellular Ca2+ overload, immunogenic cell death, and activation of the STING pathway. This resulted in a substantial reprogramming of the tumor microenvironment and the initiation of a robust tumor metalloimmunotherapy response.