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A computational framework for designing micron-scale crisscross DNA megastructures

Aquilina, M.; Katzmeier, F.; Nijenhuis, M.; Wang, S.; Becker, C.; Zhao, Y.; Seok, S. H.; Finkel, J.; Cui, H.; Lee, J.; Lee, S.; Shih, W.

2026-01-24 synthetic biology
10.64898/2026.01.23.701435 bioRxiv
Show abstract

Crisscross polymerization enables the assembly of hundreds of unique DNA origami slats into micron-sized structures with nanoscale precision. To design these megastructures, thousands of handle sequences from a fixed library must be assigned to individual slats to encode the desired binding architecture. This complexity presents two major challenges: handles must be selected to minimize parasitic interactions that compete with desired assembly, and the fabrication of hundreds of unique slats creates a substantial logistical burden. Here, we develop a unified framework that standardizes the design and fabrication of crisscross megastructures. We use an evolutionary algorithm to optimize handle assignment and minimize parasitic binding between slats, paired with a graph-based algorithm that expands the handle library. Together, these algorithms enable the assembly of large, multi-layered megastructures that otherwise would be produced at negligible yields. We have released this framework as #-CAD, an open-source graphical application that integrates these algorithms, streamlines laboratory workflows, and makes crisscross DNA origami more broadly accessible.

Published in Nature Communications (predicted rank #1) · training set

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