De Novo Design of Targeted Drugs by Precisely Programming Multiple Molecular Binding

Abstract

Targeted drug discovery has enabled the development of effective therapies for many diseases. However, a fundamental challenge remains in translating molecular binding into functional performance for the development of novel targeted drugs. Here, we present a programmable DNA nanoframe (NF) strategy that converts ligand binding into robust biological functions through precise spatial organization of multiple ligands. By encoding target dimensions and binding geometry, we have successfully constructed potential targeted nanodrugs against diverse proteins, which exhibit high avidity with markedly enhanced binding affinity and selectivity. A design-driven blockade of VEGF has also been translated into marked antiangiogenic efficacy both in vitro and in vivo. Overall, the programmable DNA NFs establish a modular and generalizable paradigm for targeted drug design, upgrading weak or non-functional binders into effective inhibitors through rational spatial programming.