Fluorophores that exhibit superior photostability have vast applications, ranging from long-term in vivo tracking to cellular super-resolution imaging. Herein, we showcased a promising buffering strategy that significantly enhanced the photostability of the near-infrared (NIR) emissive heptamethine cyanine (Cy7) by simply employing a water-responsive oxa- zolidine (Ox) switch to cage the Cy7 scaffold. This switch established an equilibrium between nonfluo- rescent closed form (CF) and fluorescent open form (OF) isomers that effectively compensated for the loss of OF due to photobleaching. Proven effective in both in vitro and in vivo contexts, this strategy markedly improved the durability and utility of Cy7 for sophisticated imaging techniques, including sta- ble NIR tumor imaging in live mice and mitochondrial super-resolution imaging, thereby paving the way for enhanced bioimaging capabilities even under intense laser irradiation.

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