The advances in fluorescence microscopy-based single virion binding and fusion assays have provided important insights into the understanding of binding and fusion of pathogenic viruses, such as Influenza, Zika, or SARS-CoV-2. In these assays a solid-supported bilayer membrane or tethered lipid vesicles serve as target membranes mimicking the host cell membrane. Thanks to the sensitivity of fluorescence microscopy, this enables tracking the dynamic behavior of virus-membrane interactions as well as lipid mixing or content release during the fusion; importantly, with single virus particle resolution. Despite the relevance of single virion assays in virology, the usage of fluorescence as a readout comes with intrinsic limitations. First, the virus or the target membrane is required to be equipped with exogenous dyes as fluorescent labels, which can impair viral activity or impact physicochemical properties of the membrane, respectively. Second, despite enabling the detection of single particles, fluorescence does not provide direct molecular information on the underlying biomolecular interactions or structural changes. These drawbacks motivate the development of new methods to complement fluorescence-based assays.