Biomolecular Condensates as Protein Degradation Tools for Intracellular Targets

SHORT DESCRIPTION
A targeted-protein degradation platform for intracellular targets, addressing resistant oncogenic and neurodegenerative targets.

• Shana Kelley*
  • Weinberg College of Arts & Sciences, Department of Chemistry
• Yi Li

NU 2025-050

IP STATUS

PCT Application has been filed (PCT/US2026/020843)

DEVELOPMENT STAGE

TRL-4: Component/Formulation Validation – Successfully validated in a xenograft tumor model showing effective mutant-specific protein degradation in vivo.

BACKGROUND
Targeted protein degradation (TPD) leverages cellular protein degradation systems to eliminate pathogenic proteins that lead to various diseases, including cancer and neurodegenerative disease. Given that many disease-causing proteins reside intracellularly, it is imperative to develop intracellular TPD tools. Current methods for intracellular protein targeting are hindered by inefficient delivery and limited specificity. Antibody therapies struggle to penetrate cell membranes and often cause off-target effects. There is a pressing need for platforms that improve intracellular antibody delivery to target proteins considered “undruggable” to enable novel therapeutic approaches for cancer and neurodegenerative diseases. 

ABSTRACT
Northwestern researchers have developed a novel platform for intracellular targeted protein degradation. This approach leverages liquid-liquid phase separation (LLPS) to condense antibodies into biomolecular condensates (BMCs). These condensates are further stabilized by metal–phenolic network (MPN) coatings, and by incorporating cell-penetrating and proteasome-recruiting peptides, these coated condensates enable the precise targeting and degradation of disease-specific intracellular proteins via the proteasome pathway. This approach demonstrates high specificity, selectively degrading mutant KRAS without affecting wild-type variants. In vivo studies reveal significant tumor suppression with minimal off-target effects, validating its therapeutic potential. Additionally, the platform provides modularity for targeting various intracellular proteins by using interchangeable antibody warheads. This platform represents a groundbreaking advance in precision medicine, offering a safe and versatile approach for treating diseases previously considered undruggable. The platform's high specificity, modularity, and in vivo efficacy make it a powerful and versatile tool in the field of protein degradation and for the treatment of diseases with elevated intracellular pathogenic proteins.

APPLICATIONS

• Precision oncology: Enables targeted degradation of oncogenic proteins (e.g., KRas G12V) with high specificity, minimizing off-target effects.
• Neurodegenerative diseases: Facilitates intracellular degradation of α-synuclein and similar aggregating proteins, providing a therapeutic option for diseases like Parkinson’s and Alzheimer’s.
• Intracellular drug delivery: Serves as a versatile platform for intracellular transport of therapeutic antibodies, overcoming limitations of traditional drug delivery systems.
• Cancer therapy enhancement: Supplements existing treatments through targeted tumor suppression.
• Prototyping therapeutics for undruggable targets: Expands the toolkit for addressing proteins lacking conventional binding sites.

ADVANTAGES

• Improved intracellular delivery: Bypasses membrane barriers to deliver intact antibodies inside cells.
• High specificity for mutant targets: Achieves selective degradation while sparing wild-type proteins.
• Modular and adaptable design: Easily tailored for a broad spectrum of intracellular targets by incorporating different antibody warheads.
• Proven in vivo efficacy: Demonstrates significant tumor suppression and favorable safety profile in xenograft models.

CATEGORY/INDUSTRY PIPELINE
Therapeutics; Biomarkers & Biomedical Research Tools

KEYWORDS
Biomolecular Condensates, Intracellular Protein Degradation, Targeted Protein Degradation, Antibody Delivery, Liquid-Liquid Phase Separation, Metal-Phenolic Networks, Proteasome Recruitment, Cancer Therapy, Neurodegeneration, Neurodegenerative Disease, Intracellular Drug Delivery, Platform Technology, Therapeutics