Stanton, A. E.; Kang, J.; Blanchard, J. W.; Boix, C. A.; Schroeder, M. E.; Lee, Y.; Su, H.; Wang, S.; Yu, E.; Emenari, A.; Peng, Z.; Agbas, E.; Cerit, O.; Park, D.; Zhang, R.; Bennett, D. A.; Yin, P.; Kellis, M.; Langer, R.; Boyden, E.; Tsai, L.-H.

Expansion revealing (ExR) elucidates cellular organization by separating proteins within dense nanostructures by 20x linear expansion, but requires fixation procedures incompatible with human pathology specimens. Here, we report ExR of pathology (ExRPath), which attains ~20 nm resolution and decrowding of such tissues, through iterative 20x expansion, adapted to human brain pathology specimens. We also report a single-shot 15x expansion protocol for such tissues (15ExMPath), achieved through one-shot 15x expansion. Applying ExRPath and 15ExMPath to COVID-19-decedent brain tissue reveals periodic amyloid nanoclusters that co-localize with SARS-CoV-2 in a rare minority of patient specimens, pointing to a potential neuroinflammatory phenotype associated with COVID-19, and highlighting the power of high-throughput nanoimaging, empowered by expansion microscopy, for discovering potential novel disease mechanisms.