Lipids are fundamental building blocks of cells and their organelles, yet nanoscale resolution imaging of lipids has been largely limited to electron microscopy techniques. We introduce and validate a chemical tag that enables lipid membranes to be imaged optically at nanoscale resolution via a lipid-optimized form of expansion microscopy, which we call membrane expansion microscopy (mExM). mExM, via a novel post-expansion antibody labeling protocol, enables protein-lipid relationships to be imaged in organelles such as mitochondria, the endoplasmic reticulum, the nuclear membrane, and the Golgi apparatus. mExM may be of use in a variety of biological contexts, including the study of cell-cell interactions, intracellular transport, and neural connectomics.
