Here, an integrated cascade nanozyme with a formulation of Pt@PCN222-Mn is developed to eliminate excessive reactive oxygen species (ROS). This nanozyme mimics superoxide dismutase by incorporation of a Mn–[5,10,15,20-tetrakis(4-carboxyphenyl)porphyrinato]–based metal-organic framework compound capable of transforming oxygen radicals to hydrogen peroxide. The second mimicked functionality is that of catalase by incorporation of Pt nanoparticles, which catalyze hydrogen peroxide disproportionation to water and oxygen. Both in vitro and in vivo experimental measurements reveal the synergistic ROS-scavenging capacity of such an integrated cascade nanozyme. Two forms of inflammatory bowel disease (IBD; i.e., ulcerative colitis and Crohn’s disease) can be effectively relieved by treatment with the cascade nanozyme. This study not only provides a new method for constructing enzyme-like cascade systems but also illustrates their efficient therapeutic promise in the treatment of in vivo IBDs.

Safe, effective, and convenient administration of therapeutic nanomaterials is one of the greatest difficulties in nanomedicine. To tackle this challenge, a system which couples multi-enzyme mimicking CeO 2 nanoparticles with clinically approved montmorillonite (MMT) for inflammatory bowel disease (IBD) therapy is reported. CeO 2 exhibits superoxide dismutase-and catalase-like activities, and hydroxyl radical scavenging activity, making it more efficient at scavenging reactive oxygen species (ROS) than noncatalytic antioxidants while being more stable than free enzymes. In addition, negatively-charged MMT can be orally administered and specifically adsorbed onto positively-charged inflamed colon tissue via electrostatic interactions for targeted delivery. When the two are assembled together by in situ growth of CeO 2 onto MMT, the optimized CeO 2 @MMT(1:9) is stable in the stomach for oral delivery, targets the inflamed colon through electrostatic interactions, and reduces inflammation through ROS scavenging, all without any significant systemic exposure as demonstrated by the relief of murine IBD in vivo.

Nanozyme is a collection of nanomaterials with enzyme-like activity but higher environmental tolerance and long-term stability than their natural counterparts. Improving the catalytic activity and expanding the category of nanozymes are prerequisites to complement or even supersede enzymes. However, the development of hydrolytic nanozymes is still challenged by diverse hydrolytic substrates and following complicated mechanisms. Here, two strategies are informed by data to screen and predict catalytic active sites of MOF (metal–organic framework) based hydrolytic nanozymes: (1) to increase the intrinsic activity by finely tuned Lewis acidity of the metal clusters; (2) to improve the density of active sites by shortening the length of ligands. Finally, as-obtained Ce-FMA-MOF-based hydrolytic nanozyme is capable of cleaving phosphate bonds, amide bonds, glycosidic bonds, and even their mixture, biofilms. This work provides a rational methodology to design hydrolytic nanozyme, enriches the diversity of nanozymes, and potentially sheds light on future evolution of enzyme engineering.