Expansion Revealing of Pathology Resolves Nanostructures Associated with Inflammatory Phenotypes in COVID-19 Decedent Human Brain Tissue

Alice E. Stanton; Jinyoung Kang; Joel Blanchard; Carles A. Boix; Margaret E. Schroeder; Y S Lee; Hanquan Su; Shiwei Wang; Eunah Yu; Amauche Emenari; Zhuyu Peng; Emre Agbas; Oyku Cerit; Demian Park; Ruihan Zhang; David A. A Bennett; Peng Yin; M Kellis; Róbert Langer; Edward S. Boyden; Li‐Huei Tsai

doi:10.64898/2026.05.14.725177

NeurosciencebioRxivMay 15, 2026

Preprint

Expansion Revealing of Pathology Resolves Nanostructures Associated with Inflammatory Phenotypes in COVID-19 Decedent Human Brain Tissue

Alice E. Stanton iD, Jinyoung Kang iD, Joel Blanchard iD, Carles A. Boix iD, Margaret E. Schroeder iD, Y S Lee, Hanquan Su iD, Shiwei Wang, Eunah Yu iD, Amauche Emenari, Zhuyu Peng iD, Emre Agbas, Oyku Cerit iD, Demian Park, Ruihan Zhang iD, David A. A Bennett iD, Peng Yin iD, M Kellis iD, Róbert Langer iD, Edward S. Boyden iD, Li‐Huei Tsai iD

Abstract

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.

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