Simulation‐Guided Rational Design of DNA Walker‐Based Theranostic Platform

Abstract Biomolecule‐functionalized nanoparticles represent a type of promising biomaterials in biomedical applications owing to their excellent biocompatibility and versatility. DNA‐based reactions on nanoparticles have enabled emerging applications including intelligent biosensors, drug delivery, and biomimetic devices. Among the reactions, strand hybridization is the critical step to control the sensitivity and specificity of biosensing, and the efficiency of drug delivery. However, a comprehensive understanding of DNA hybridization on nanoparticles is still lacking, which may differ from the process in homogeneous solutions. To address this limitation, coarse‐grained model‐based molecular dynamic simulation is harnessed to disclose the critical factors involved in intermolecular hybridization. Based on simulation guidance, DNA walker‐based smart theranostic platform (DWTP) based on “on‐particle” hybridization is developed, showing excellent consistency with simulation. DWTP is successfully applied for highly sensitive miRNA 21 detection and tumor‐specific miRNA 21 imaging, driven by tumor‐endogenous APE 1 enzyme. It enables the precise release of antisense oligonucleotide triggered by tumor‐endogenous dual‐switch miRNA 21 and APE 1, facilitating effective gene silencing therapy with high biosafety. The simulation of “on‐particle” DNA hybridization has improved the corresponding biosensing performance and the release efficiency of therapeutic agents, representing a conceptually new approach for DNA‐based device design.