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<p>Targeted protein degradation harnesses endogenous cellular machinery to eliminate disease-causing proteins, yet achieving phenotype-specific degradation across diverse cell types remains challenging. Here we show that antibody-enriched biomolecular condensates formed by liquid–liquid phase separation function as intracellular protein degradation tools, combining cytosolic trafficking with direct proteasome recruitment for targeted substrate clearance. These nanoscale condensates incorporate a short proteasome-targeting motif into phase-separation precursors, preserve antibody activity, enable direct proteasome recruitment, and improve delivery uniformity. When loaded with a mutation-specific antibody, these condensates selectively degrade oncogenic KRAS G12V without affecting wild-type KRAS in heterozygous cells, and suppress tumor growth in a KRAS G12V xenograft model. This strategy provides a modular platform for intracellular protein degradation that can be readily adapted by exchanging antibodies, without requiring genetic modification of cellular system.</p>

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Biomolecular Condensates as Protein Degradation Tools for Intracellular Targets

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月13日

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  • Yi Li,
  • Zhicheng Jin,
  • Sharif U. Ahmed,
  • Jagotamoy Das,
  • Reiner Bleher,
  • Dingran Chang,
  • Xiaozhou Yu,
  • Connor D. Flynn,
  • Jiajing Zhou,
  • Xiaobing Hu,
  • Kangfu Chen,
  • Kimberly T. Riordan,
  • Ranjit Atwal,
  • Julia M. Mayes,
  • Zongjie Wang,
  • Shana O. Kelley

摘要

Targeted protein degradation harnesses endogenous cellular machinery to eliminate disease-causing proteins, yet achieving phenotype-specific degradation across diverse cell types remains challenging. Here we show that antibody-enriched biomolecular condensates formed by liquid–liquid phase separation function as intracellular protein degradation tools, combining cytosolic trafficking with direct proteasome recruitment for targeted substrate clearance. These nanoscale condensates incorporate a short proteasome-targeting motif into phase-separation precursors, preserve antibody activity, enable direct proteasome recruitment, and improve delivery uniformity. When loaded with a mutation-specific antibody, these condensates selectively degrade oncogenic KRAS G12V without affecting wild-type KRAS in heterozygous cells, and suppress tumor growth in a KRAS G12V xenograft model. This strategy provides a modular platform for intracellular protein degradation that can be readily adapted by exchanging antibodies, without requiring genetic modification of cellular system.