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Here, we demonstrate that zinc finger (ZF) proteins function as programmable interaction units that modulate neurodegenerative amyloid liquid\u2013liquid phase separation, redirect \u03b2\u2010sheet\u2010rich fibrillation toward nontoxic assemblies, and actively disassemble preformed fibrils. Multiscale investigations spanning molecular, cellular, and organismal levels reveal that tandemly arrayed ZF modules mediate direct, high\u2010affinity protein\u2013protein interactions, thereby mitigating amyloid pathogenicity. Through modular protein engineering, these protective effects translate in vivo, where a brain\u2010penetrant ZF variant reduces amyloid deposition, suppresses neuroinflammatory responses, and improves cognitive performance in Alzheimer's disease transgenic mice. Furthermore, sequence\u2013structure\u2013function analyses identify key determinants governing amyloid assembly control, offering mechanistic principles for ZF\u2010inspired protein engineering. Collectively, this work positions ZF proteins as versatile, chemically programmable platforms for engineering protein\u2010based materials that regulate biomolecular phase behavior and toxicity, expanding their functional scope beyond traditional genetic regulation toward therapeutic applications.<\/jats:p>","DOI":"10.1002\/advs.77886","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T08:22:01Z","timestamp":1790756521000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Zinc Fingers as Programmable Metalloprotein Scaffolds for Altering Pathogenic Biomolecular Phase Transitions"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1030-4935","authenticated-orcid":false,"given":"Seongmin","family":"Park","sequence":"first","affiliation":[{"name":"Department of Chemistry Korea Advanced Institute of Science and Technology (KAIST)  Daejeon Republic of 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