Under what conditions does the perceived "unnaturalness" of a specific application of synthetic biology influence its public acceptability? Using data from a framing experiment embedded in a national survey of Canadian adults, we argue that this consideration leads to negative perceptions of the technology only when opponents of the application use rhetoric that refers to its unnaturalness and when characteristics of the application itself, such as the use of genetic material from "dissimilar" organisms, increase the perceived relevance of such arguments. Additionally, we find that individuals who view nature as sacred or spiritual are most responsive to unnaturalness framing.