Novel synthetic biomolecular condensates have been developed that can degrade intracellular oncogenic protein KRAS. Recently, researchers at Northwestern Medicine (IL, USA) developed a synthetic biomolecular condensate that can deliver targeted antibodies to degrade intracellular disease-causing proteins. This novel modular platform is adaptable, overcoming the challenge posed by variations in protein structure across different cell types. The study paves the way for future therapeutics development and demonstrates biomolecular condensates’ potential as a programmable biomaterial. Targeted protein degradation (TPD) is a therapeutic strategy that relies on cells’ own degradation machinery to break down and expel pathogenic proteins. Despite recent success with phenotype-specific TPD targeting certain KRAS mutants – oncoproteins that drive tumorigenesis – there remains an urgent need for therapeutics that can address a broader range of KRAS mutations. To address this need, the researchers turned to biomolecular condensates, which are dynamic, membrane-less structures involved in many cellular functions, including RNA metabolism and DNA damage response. Harnessing this natural capability and combining it with the specificity of antibodies, they developed peptidic IgG condensates assembled using liquid–liquid phase separation, incorporating a short proteasome-targeting motif and stabilized with metal–phenolic network shells. The platform can conduct antibody-guided variant-selective degradation and recruit proteasomes to help it adapt to diverse targets, overcoming the limitations of previous TPD strategies. Partnered with a KRAS mutation-specific antibody in heterozygous cells, their condensate selectively degraded the KRAS G12V variant, a protein with a distinct structure prevalent across multiple cancers that lacks selective targeted therapies. It achieved this without affecting wild-type phenotypes.…
