High‐Entropy Metal–Organic Cages as Multienzyme Mimetics for the Mitigation of Acute Kidney Injury

ABSTRACT Precise morphological and compositional regulation of high‐entropy nanoparticles (HENPs) represents a fundamental prerequisite for advancing their applications in catalysis and electronics. Conventional synthesis approaches, however, face challenges stemming from intrinsic elemental segregation dynamics and the unpredictable atomic configurations within individual nanoparticles. To address this, we introduce an isostructural substitution strategy for constructing HENPs, utilizing predefined molecular scaffolds to guide multielemental integration. By employing a calixarene‐based octahedral metal–organic cage (MOC) featuring six well‐defined M 4 O clusters (totaling 24 metal sites) as a structural template, we systematically incorporate five distinct metallic elements (Mg, Mn, Co, Ni, Zn) through solvothermal synthesis, yielding high‐entropy MOC (HEMOC) nanoobjects in gram scale. These engineered HEMOCs preserve the octahedral skeleton and structural uniformity, maintain readily accessible catalytic centers with tunable stoichiometry, and exhibit exceptional aqueous‐phase stability. Significantly, the diverse heterometallic M 4 O clusters within HEMOCs function as cluster nanozymes, demonstrating amplified multienzyme‐mimetic catalytic activity for scavenging reactive oxygen species. Demonstrating favorable biocompatibility profiles in biological evaluations, the optimized HEMOCs successfully attenuate inflammation in acute kidney injury models, suggesting therapeutic potential for oxidative stress‐associated pathologies.