A robust metal–organic framework-based nanozyme with multienzyme-like properties for synergistic tumor therapy via efficient and sustainable Nitric oxide generation

Nitric oxide (NO)-based gas therapy represents an emerging strategy for cancer treatment, which, however, still suffers from insufficient intracellular NO production for compromised therapeutic efficiency due to limited endogenous hydrogen peroxide (H₂O₂) concentration and relatively slow NO generation rate. The use of metal-organic framework (MOF) with highly ordered porous structure and functional adjustability to design a multienzyme-like nanozyme provides a simple yet reliable approach for efficient and sustainable NO generation. Herein, a MOF-based nanozyme with multienzyme-like properties is constructed by depositing ultrasmall gold nanoparticles (Au NPs) and subsequently loading a NO donor, l-arginine (l-Arg) on an iron porphyrin integrated MOF, which enables efficient and sustainable NO generation for synergistic tumor therapy. Two notable merits of this design are (i) incorporation of Au NPs with glucose oxidase (GOx)-like property for effectively depleting intratumoral glucose, and simultaneously generating large amounts of H₂O₂, which is further utilized to initiate the effective production of NO and reactive oxygen species (ROS) by taking advantage of the peroxidase (POD)/NO synthase (NOS)-like activities of iron porphyrin, and (ii) deposition of ultrasmall Au NPs on the MOF for remarkably improving the structural stability of nanocomposites to circumvent the low catalytic efficiency associated with serious aggregation. This nanozyme achieves a high tumor inhibitory rate of 87.3 % with negligible systemic effects in a 4T1-tumor-bearing mice model by integrating NO, and ROS generation and starvation therapy with synergistic efficiency. Such an ingenious integration of multienzyme-like nanozyme and MOF paves a new way for NO-based gas therapy.