Shih's lab standardizes the design of crisscross DNA megastructures in software

Each join in one of these structures is a short "handle" sequence that ties a set position on a slat in one grid layer to the corresponding position on a slat in the next, working, in the group's description, like molecular Velcro ^[3]. Every layer added brings another set of those pairings, and each one has to find its own partner and ignore the rest ^[2]. "The challenge of avoiding unwanted DNA binding events in self-assembling DNA nanostructures just becomes magnified enormously in the fabrication of crisscross DNA megastructures," said Shih, a founding core faculty member at the Wyss Institute and professor of biological chemistry and molecular pharmacology at Harvard Medical School and Dana-Farber ^[7][8].

The distinction he is drawing is between a demonstration and a method. "However, there is a difference between demonstrating that something can be done in principle and enabling it to be done with high efficiency, with very low error rates and in many more research labs," he said ^[6].

Crisscross polymerization was introduced in 2021 ^[4]. The report on the design framework carries a September 2026 date ^[13], five years on ^[14]. It describes the framework as standardizing design and fabrication but does not report assembly yields, error rates, or a comparison with hand-designed structures ^[18]. The framing of design as the limiting step is Shih's own. Testing it would take an error rate measured by an outside lab.

The applications are prospective. Shih listed "optical devices that can modulate light at visible wavelengths" and scaffolds "for assembling tissues with programmable shapes and functions" among what micrometer-scale structures with nanoscale features could open up ^[9]. The group has also raised diagnostics in which a rare disease biomarker in a patient sample kickstarts a fast crisscross reaction, and the nanoribbon that grows is the readout ^[16].

One origami application is further along. It has nothing to do with megastructures. The Wyss Institute's DoriVac project, led by Shih, used DNA origami to organize vaccine components at the nanoscale to strengthen immune activation against cancer ^[15]. Shih's group is also the one that took the original 2D origami idea into 3D multilayered geometries, making structures that are more stable, rigid and resilient in harsh chemical and biological environments ^[11].