NanoMetaboGate: Dual Creatine‐Axis Blockade and Immune Reprogramming for Integrated Glioblastoma Therapy

ABSTRACT Glioblastoma (GBM) exhibits profound tumor metabolic plasticity and an immunosuppressive, macrophage‐rich microenvironment, leading to poor and short‐lived therapeutic responses. Here, we report nanoMetaboGate, a pH‐responsive nanoplatform that couples metabolic restriction with immune remodeling. A macrophage‐GBM hybrid membrane coating enables immune evasion, homotypic targeting, and blood‐brain barrier penetration. In acidic GBM tissue, the ZIF nanocore disassembles to release Zn 2+ and the creatine‐uptake inhibitor guanidinopropionic acid (GPA), establishing a dual checkpoint blockade of the creatine metabolic axis. Zn 2+ attenuates macrophage glycolysis to alleviate immunosuppression and reduce creatine supply, while GPA inhibits creatine uptake in GBM cells, diminishing stem‐like traits. Meanwhile, Zn 2+ triggers cGAS‐STING activation, together with creatine limitation, synergistically enhances oxidative injury. Collectively, these coordinated actions disrupt metabolic buffering, remodel the suppressive niche, and promote tumor cell death. This work pioneers a GBM‐tailored strategy leveraging ion‐assisted metabolic intervention for improved therapeutic control.