Biomolecular Condensates as Protein Degradation Tools for Intracellular Targets.

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.