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have by now progressed to several other protein origami shapes with different chemical properties,” said Jerala. “We plan to use these as cages to encapsulate different types of molecular cargo and guide the delivery of those cages to different cell types.” Opening and closing of cages might be regulated by mechanisms that respond to different chemical conditions, such as pH, salt concentration, or the presence of certain enzymes. Jerala’s team also sees these cages, which resemble viral capsids, as potentially useful for vaccine design or for replacing aberrant enzymes or other dysfunctional cellular components that cause disease. Entering the Clinic Before these constructs can be used clinically, investigators must overcome considerable challenges in loading them, protecting them from degradation or excretion, and targeting them to specific tissues or cells. “Recently we’ve validated a cationic polymer coating that provides significant protection for DNA nanostructures against low-salt denaturation and nuclease digestion,” said Shih. Although DNA and protein origami is not yet ready for use in patients, a more immediate impact may lie in its potential as custom instruments for answering biological questions. For example, constructs may be formed to hold proteins in positions and orientations to help scientists image them with various microscopy techniques, and Shih’s use of DNA-based springs can help researchers measure the speed and properties of protein motors. Still others have fashioned origami into nanoscale pores that can provide information on molecules that pass through them. These might be used to help characterize protein-DNA and protein-protein interactions involved in normal or aberrant cellular processes. “All of these are not direct clinical applications but rather enable fundamental biological science that will eventually end up in the clinic,” said Rothemund.