Recent advances in super-resolution fluorescence microscopy have led to ∼10 nm spatial resolution and profound impact on cell biology and beyond. Here we discuss emerging possibilities to encode functional information of intracellular microenvironments, for example, local pH, small-molecule concentrations, chemical polarity (hydrophobicity), and protein activity, into diverse dimensions of the super-resolution signal, hence a class of approaches we collectively refer to as functional super-resolution microscopy. By adding remarkably rich functional information to the already powerful super-resolution arsenal, functional super-resolution microscopy transcends the structural information provided by existing methods, and opens up new ways to unveil fascinating local heterogeneities in live cells with nanometer-scale spatial resolution and ultimate sensitivity down to the single-molecule level.
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