An In Situ Self‐Responsive Nano‐Prodrug to Enable Tumor Chemo‐Metalloimmunotherapy

Abstract Chemotherapy remains a mainstream cancer therapy but is hindered by severe side effects and limited durable cancer control. Smart nanomedicines that integrate prodrug delivery and immune modulation may offer potential opportunities to tackle the daunting challenges. Herein, an acid‐responsive nanocarrier (ZZTA) consisting of ZnO 2 , ZIF‐8, and Zn‐tannic acid is developed. A phenylboronic ester prodrug (BDOX) is synthesized and integrated with ZZTA, creating a multifunctional nano‐prodrug, ZZTA‐BDOX. The yolk‐shell structure of ZZTA prevents premature decomposition of ZnO 2 during circulation, and enables sustained release of Zn 2+ and H 2 O 2 in response to the acidic tumor microenvironment. The generated H 2 O 2 subsequently activates BDOX, releasing cytotoxic DOX intracellularly. Meanwhile, the Zn 2+ released enhances cGAS‐STING signaling, promoting dendritic cell maturation and T cell priming, which results in clear systemic antitumor immune responses. The in vivo study demonstrates that ZZTA‐BDOX nano‐prodrug not only enables efficient tumor inhibition but also suppresses metastasis through immune activation.