Coacervate-Mediated Lysosome-Targeting Antibody Delivery for Protein Degradation

Area of Science:

• Biochemistry
• Cell Biology
• Nanotechnology

Background:

• Antibody-based cancer therapies target cancer-associated proteins (CAPs) for degradation within lysosomes.
• Efficiently delivering antibody-CAP complexes into cells and specifically to lysosomes remains a challenge.
• Existing phase-separating coacervates can enter cells but lack lysosomal targeting.

Purpose of the Study:

• To design novel coacervates capable of targeting lysosomes for protein degradation.
• To develop a new therapeutic strategy for cancer treatment by degrading CAPs.
• To enhance the efficacy of existing protein degradation technologies like PROTACs.

Main Methods:

• Tailoring a tetrapeptide to create phase-separating Lysosome-Sorting Peptide Coacervates (LSP-Coa) via liquid-liquid phase separation (LLPS).
• Demonstrating spontaneous cellular uptake and lysosomal colocalization of LSP-Coa.
• Utilizing LSP-Coa to encapsulate antibody-CAP complexes for lysosomal delivery and degradation (Coacervate-mediated Lysosome-targeting Protein Degradation - CoaLPD).

Main Results:

• LSP-Coa effectively encapsulate proteins and facilitate translocation of antibody-CAP complexes to lysosomes.
• CoaLPD successfully degraded membrane-bound CAPs, including HER2 and EGFR, in cancer cells and in vivo tumor models.
• The LSP-Coa system enhanced lysosomal uptake and improved the efficacy of PROTAC-mediated degradation.

Conclusions:

• Lysosome-targeting coacervates (LSP-Coa) have been successfully designed and synthesized.
• The CoaLPD strategy provides a novel mechanism for targeted degradation of CAPs, showing potential as an anticancer treatment.
• LSP-Coa serve as effective vehicles for lysosome-specific antibody delivery, advancing targeted protein degradation therapies.