Efficiency of Protease-Activatable Virus Nanonodes Tuned Through Incorporation of Wild-Type Capsid Subunits

Virus nanonodes, a tunable multi-input protease-responsive gene delivery platform, was recently built by exploiting the self-assembly property of adeno-associated virus capsids. Upon detection of specific inputs (e.g., matrix metalloproteinases-MMPs), the engineered viruses output gene delivery to targeted cells. The first generation protease-activatable viruses (PAVs) displayed the desired protease-activated cellular receptor binding and transduction behaviors. However, the less than wild type (WT) level of gene delivery achieved by the prototype viruses has left room for improvement. In this report, we have devised a method to tackle this efficiency problem. Specifically, by controlling the ratio of WT to protease-activatable subunits in the assembled 60-mer virus capsid, we can easily increase the level of overall transduction achieved by the PAVs. Since a number of MMPs are overexpressed in a vast range of human pathologies, including cancer and cardiovascular disease, the protease-sensing viruses may find broad clinical use in future gene therapy applications.