Alzheimer’s disease (AD) is the most common form of dementia, affecting over 55 million people worldwide and characterized by progressive memory loss, cognitive decline, and neuronal dysfunction. A central hallmark of AD is the excessive accumulation of amyloid-beta (Aβ) peptides, which arise when the β-secretase 1 (BACE1) enzyme cleaves the amyloid precursor protein (APP). Inhibiting BACE1 represents a promising therapeutic strategy to reduce Aβ formation and slow disease progression. In this study, we designed and evaluated aptamer-mediated DNA origami nanostructures for the targeted inhibition of BACE1 using a computational pipeline. DNA origami was employed as a nanotechnology platform to create customizable 2D and 3D structures capable of delivering aptamers to their target. Using Cadnano software, scaffold and staple routes were mapped, exported as .json files, and then converted into 3D .pdb structures via cadnano2pdb. The models were visualized and verified in ChimeraX, enabling nanoscale precision in structure folding. These DNA origami frameworks provided a stable carrier for aptamers designed to bind BACE1. Molecular docking and binding energy analysis revealed that aptamer A2 integrated within the DNA origami system exhibited the strongest interaction with BACE1, showing a binding energy of –528.12 kJ/mol, surpassing A4 and mutant aptamers. The integration of DNA origami scaffolds with aptamers highlights a novel strategy for selectively inhibiting BACE1 and reducing amyloid-beta production. This computational framework underscores the potential of DNA origami–guided aptamer therapies as next-generation nanomedicine tools for Alzheimer’s disease treatment.

Gaurav Sharma

Eigen Sciences

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