CompartmentalizedNanozyme–Enzyme Cascade EnablesMetabolic–Redox Coupling for Acute Kidney Injury Therapy

Abstract Acute kidney injury (AKI) presents a recalcitrant pathological network where metabolic dysfunction and oxidative stress are intrinsically coupled requiring more than single-target intervention. Herein, we report the rational design of UL-Gel, a core–shell compartmentalized nanozyme–metabolic enzyme cascade microreactor for synergistic lactate depletion and reactive oxygen species scavenging. This system is constructed via enzyme-driven interfacial radical gelation, where lactate oxidase-generated H2O2 is locally relayed to the UIO-66 core to initiate polymerization, whereas elevated pathological H2O2 redirects UIO-66 toward catalase- and superoxide dismutase-like antioxidant activities. In an AKI model, UL-Gel reduced renal lactate by 69.3% and restored endogenous antioxidant enzyme activities. Transcriptomic analysis further confirmed that UL-Gel resets the renal landscape by modulating the AGE-RAGE-NOX4 and PI3K-Akt signaling axes. This work demonstrates the power of integrating dynamic nanozyme kinetics with interfacial material engineering to create smart therapeutic platforms for complex metabolic diseases.