Zinc-coordination-driven mitochondrial nanodisruptors to ablate cancer stemness for potentiating immunotherapy in colorectal malignancies

Cancer stemness, sustained by mitochondrial metabolic plasticity, drives immunotherapy resistance in colorectal cancer (CRC). We reengineer zeolitic imidazolate framework-8 (ZIF-8), a zinc-coordination-driven metal-organic framework, from inert nanocarrier to a multifunctional mitochondrial synchronizer that disrupts stemness through tripartite bioenergetic targeting. A hyaluronic acid (HA)-modified nanoarchitecture (HA/ZGA) co-delivers glucose oxidase (GOx) and 5-aminolevulinic acid (5-ALA), leveraging ZIF-8's intrinsic Zn²⁺ release for dual metabolic blockade: Zn²⁺ inhibits glucose transporters and electron transport chain activity, while GOx depletes glucose to amplify energy stress. Concurrently, 5-ALA enables cristae-confined photodynamic ROS generation, collapsing oxidative phosphorylation and silencing pluripotency regulators. This metabolic triad coordinately eradicates stemness, reverses PD-L1/CD44 co-expression, and triggers cytotoxic T cell infiltration. In translational models, HA/ZGA achieves potent tumor regression, suppresses metastasis, and establishes immunological memory against rechallenge. Our work redefines ZIF-8 as a therapeutic chameleon that dismantles mitochondrial energetics, ablates stemness, and reignites antitumor immunity, exemplifying nanomaterial repurposing to bridge metabolic intervention with immune potentiation.