A Pillararene‐Based Supramolecular Nanozyme With Multivalency‐Enhanced Peroxidase‐Like Activity Triggers Pyroptosis to Activate Anti‐Tumor Immune Response

ABSTRACT Nanozymes hold potential in tumor therapy owing to their enzyme‐mimetic activities and structural robustness, yet their therapeutic efficacy is hampered by inadequate active site density and suboptimal metal utilization. To overcome these limitations, we report a supramolecular nanozyme (denoted as DCuP NP) constructed from the self‐assembly of amphiphilic pillararene‐metal complexes (DCuP), formed through coordination between 2,2'‐dipicolylamine‐perfunctionalized pillararene and Cu 2+ ions. The DCuP NP exhibits enhanced peroxidase‐like activity, demonstrating nearly 5‐fold higher catalytic efficiency toward tetramethylbenzidine and hydrogen peroxide than 3 NP, the self‐assembly structure of a monomeric analogue of DCuP. Surprisingly, compared to 1 , the catalytic site model complex, it accomplished a remarkable amplification in peroxidase‐like activity, going from negligible to pronounced catalytic performance. Furthermore, DCuP NP amplifies oxidative stress by catalyzing hydrogen peroxide to generate reactive oxygen species and depleting glutathione in vitro, suppressing cancer cell proliferation while activating caspase 1/gasdermin D‐mediated pyroptosis, and then evoking immune responses. In 4T1 tumor‐bearing mice, DCuP NP achieves 86.5% tumor suppression with a concurrent 12.7‐fold increase in tumor‐infiltrating CD8⁺ T cells. Our work pioneers the integration of pillararene and its multivalency with metal coordination to construct supramolecular nanozymes with biocatalytic functionality, offering a novel strategy for developing simple yet efficient biomimetic nanozymes.