Self‐Assembly of 2D Polyphthalocyanine in Lysosome Enables Multienzyme Activity Enhancement to Induce Tumor Ferroptosis

Abstract Nanozymes show great potential in facilitating tumor ferroptosis by upregulation of reactive oxygen species (ROS) and downregulation of glutathione (GSH). However, mild acidity (pH 6.5–6.9) of tumor microenvironment severely restricts the activity of nanozymes. Although lysosomes as acidic organelles (pH = 3.5–5.5) are hopeful for improving enzyme‐like activity, most reported nanozymes are not capable of effectively accumulating in the lysosomes. Herein, an acid‐responsive self‐assembly strategy based on iron phthalocyanine‐rich covalent organic framework nanosheets (COF FePc NSs) is developed, which enables lysosomal targeting aggregation of COF FePc NSs due to the existence of abundant negative hydroxyl groups and rigid structure. Meanwhile, COF FePc NSs display exceptional multienzyme‐mimic performance at lower pH to efficiently generate ROS to cause lysosome damage and apoptosis by synergistic photothermal effect. Subsequently, the released COF FePc with GSH oxidase‐mimicking activity can consume GSH to promote ferroptosis. This is the first report of a 2D COF using its own properties to achieve lysosomal self‐assembly. Overall, the work provides a new paradigm for the development of lysosome‐targeted nanosystems.