Adeno-associated viral (AAV) capsid is emerging as a powerful gene delivery vehicle. However, the 25-nm icosahedral nanocage’s conserved small size imposes a restrictive cargo capacity. Inspired by the geometry and assembly mechanisms observed in larger viral capsids, we report two design strategies – tandem multimerization and guide peptide grafting – to genetically alter capsid size. The two strategies result in the formation of eXtra Large AAV capsids (XL-AAVs) with 35-60 nm diameters and the ability to package recombinant AAV genomes. These design principles can be applied to multiple AAV serotypes. The design of XL-AAVs may open the door to AAV vectors with expanded cargo capacity and provide an exemplar for the rational expansion of protein nanocages.

Bioinspired design of adeno-associated viral capsids with expanded sizes

ACS Fall 2020 Virtual Meeting

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