To enhance silencing and avoid off-target effects, siRNAs are often designed with an intentional bias to ensure that the end of the siRNA that contains the guide strand 5¢ end is less stably hybridized relative to the end containing the passenger strand 5¢ end. One means by which this is accom-plished is to introduce a terminal mismatch, typically by changing the passenger strand sequence to impair its hybridization with the guide strand 5¢ end.