Gu, P.; Chen, C.; Ren, J.

Large-scale brain imaging has relied heavily on fluorescent reporters; however, photobleaching and signal variability limit quantitative analysis in intact tissues. Here, we intro-duce MelaCAST (melanin-based scattering CAST imaging), a genetically encoded scattering strategy for whole-brain imaging. AAV-mediated delivery of tyrosinase enables cell-type-specific melanin production, generating stable intracellular scattering contrast throughout the mouse brain. By integrating tissue clearing with scattering tomography, MelaCAST enables non-photobleaching, high-throughput volumetric imaging of genetically defined cell populations in in-tact brains. This approach establishes melanin as a genetically encoded scattering reporter and expands whole-organ imaging beyond fluorescence-based modalities.