We harnessed an intrinsic activatable peptide display behavior shared by several parvoviruses, including the adeno-associated virus (AAV), in order to design protein-based nanodevices that can carry out an exogenous functional output in response to stimulus detection. Specifically, we generated truncated viral capsid subunits that, when combined with native capsid components into mosaic capsids, can perform robust activatable peptide display. By modulating the ratio of subunits in the mosaic capsid, properties of the activatable peptide display function can be optimized. Interestingly, the truncated subunits can form homomeric capsids not observed in nature, but at the price of losing the ability to carry out activatable peptide display. Collectively, our results demonstrate the importance of capsid mosaicism when activatable peptide display is desired and help explain why the wild-type AAV capsid exists as a mosaic of different subunits. This proof-of-concept study illustrates a strategy for reprogramming a particular conformational output behavior of AAV in pursuit of the long-term vision of creating stimulus-responsive nanodevices.
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