Activatable Self‐Reporting Nanoplatform for Metabolic Blockade and Cascade Amplification of Oxidative Stress

ABSTRACT The malignant proliferation of tumors is driven by profound metabolic reprogramming, which offers a critical therapeutic target. However, conventional metabolic interventions are often limited by compensatory adaptation and off‐target toxicity. Here, we designed a tumor microenvironment triggered self‐reporting nanoplatform for metabolic blockade and cascade amplification of oxidative stress. The nanoplatform was constructed by co‐assembly of a trifluoromethyl‐grafted selenium‐containing histidine ( H SeF ) with Zn 2+ and encapsulation of the metabolic blocker, phenylboronic acid‐modified cholesterol (CholB). Once in the acidic tumor microenvironment, the nanoplatform disassembles to release Zn 2+ and CholB. Zn 2+ impairs mitochondrial function to generate a burst of reactive oxygen species (ROS), while CholB triggers Gaucher disease‐like lysosomal damage that is accompanied by depletion of polyamines (key endogenous antioxidants), thereby disabling a major cellular defense and amplifying oxidative stress. Meanwhile, redox switching of H SeF is transduced into a dual‐channel 19 F MRI signal, endowing the nanoplatform with a self‐reporting capability. In a 4T1 tumor model, the nanoplatform elicited dual immune activation (cGAS‐STING and immunogenic cell death) and achieved marked tumor suppression. This work offers a self‐reporting, activatable strategy that couples metabolic blockade with cascade‐amplified oxidative stress for dual immune activation, providing a promising approach for precision cancer therapy.