DNA-Encoded Nanoparticle Interfaces Accelerate Diverse Enzymes Through Noncovalent Association

Enhancing enzyme performance without protein engineering remains a central challenge in biocatalysis. Here, we report the unusual discovery that nanoparticles densely functionalized with DNA can bind enzymes without chemical conjugation, affinity tags, or engineered recognition motifs, and substantially increase catalytic activity. This effect generalizes across multiple enzyme classes: cytochrome c and catalase exhibit ~9.4-fold and ~3.0-fold higher peroxidase activity, while carbonic anhydrase shows a ~1.6-fold increased esterase activity, underscoring the versatility of this system. Mechanistic studies indicate that enhancement is an emergent property of the three-dimensional, high-density DNA shell, with the core functioning primarily as a scaffold. Activity modulation is governed not only by DNA density and length, but also, critically, by DNA sequence, establishing sequence design as a programmable handle for tuning enzyme output. All-atom molecular dynamics simulations reveal that base-specific interactions reshape enzyme conformational flexibility and increase active-site accessibility. We further show sequence-encoded control in multienzyme systems through a DNA-programmed cascade where DNA-functionalized glucose oxidase recruits cytochrome c at the DNA interface, yielding >4.8-fold higher cascade efficiency than free-enzyme mixtures. Together, these findings position DNA-functionalized nanoparticles as adaptable, sequence-programmable platforms for improving and coordinating biocatalysis, opening new routes for enzyme control in synthesis, diagnostics, and therapeutic design.