Biomolecular Condensates as Protein Degradation Tools for Intracellular Targets
14 affiliations
- 1Department of Biomedical Engineering, McCormick School of Engineering, Northwestern University, Evanston, IL, USA
- 2International Institute for Nanotechnology, Northwestern University, Evanston, IL, USA
- 3Aiiso Yufeng Li Family Department of Chemical and NanoEngineering, University of California San Diego, San Diego, CA, USA
- 4Department of Chemistry, Weinberg College of Arts & Sciences, Northwestern University, Evanston, IL, USA
- 5The Northwestern University Atomic and Nanoscale Characterization Experimental (NUANCE) Center, Northwestern University, Evanston, IL, USA
- 6The Ken & Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
- 7Robert H. Laurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA
- 8Biohub, Chicago, IL, USA. [email protected]
- 9Department of Biomedical Engineering, McCormick School of Engineering, Northwestern University, Evanston, IL, USA. [email protected]
- 10Biohub, Chicago, IL, USA. [email protected]
- 11Department of Biomedical Engineering, McCormick School of Engineering, Northwestern University, Evanston, IL, USA. [email protected]
- 12Department of Chemistry, Weinberg College of Arts & Sciences, Northwestern University, Evanston, IL, USA. [email protected]
- 13International Institute for Nanotechnology, Northwestern University, Evanston, IL, USA. [email protected]
- 14Robert H. Laurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA. [email protected]
Abstract
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. Targeted protein degradation has huge potential, but phenotype-specific degradation remains a difficulty. Here, a phase-separation biomolecular condensates as an intracellular degradation agent is developed, combining antibody-guided recognition with direct proteasome recruitment to enable phenotype-selective protein clearance.
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BibTeX
@article{li2026biomolecular,
title = {{Biomolecular Condensates as Protein Degradation Tools for Intracellular Targets}},
author = {Y Li and Zhicheng Jin and Sharif U. Ahmed and Jagotamoy Das and Reiner Bleher and Dingran Chang and Xiaozhou Yu and Connor D. Flynn and Jiajing Zhou and Xiaobing Hu and Kangfu Chen and Kimberly T. Riordan and Ranjit Atwal and Julia M. Mayes and Zongjie Wang and Shana O. Kelley},
journal = {Nature Communications},
year = {2026},
month = may,
doi = {10.1038/s41467-026-72967-8},
url = {https://doi.org/10.1038/s41467-026-72967-8},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Biomolecular Condensates as Protein Degradation Tools for Intracellular Targets
AU - Y Li
AU - Zhicheng Jin
AU - Sharif U. Ahmed
AU - Jagotamoy Das
AU - Reiner Bleher
AU - Dingran Chang
AU - Xiaozhou Yu
AU - Connor D. Flynn
AU - Jiajing Zhou
AU - Xiaobing Hu
AU - Kangfu Chen
AU - Kimberly T. Riordan
AU - Ranjit Atwal
AU - Julia M. Mayes
AU - Zongjie Wang
AU - Shana O. Kelley
PY - 2026
DA - 2026/05/13
JO - Nature Communications
DO - 10.1038/s41467-026-72967-8
UR - https://doi.org/10.1038/s41467-026-72967-8
AB - 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. Targeted protein degradation has huge potential, but phenotype-specific degradation remains a difficulty. Here, a phase-separation biomolecular condensates as an intracellular degradation agent is developed, combining antibody-guided recognition with direct proteasome recruitment to enable phenotype-selective protein clearance.
SN - 2041-1723
ER -