Molecular Engineering of Functional DNA Molecules toward Targeted Protein Degradation

Area of Science:

• Biomedical Engineering
• Molecular Biology
• Drug Discovery

Background:

• Targeted protein degradation (TPD) is a promising therapeutic strategy for eliminating disease-causing proteins.
• A major limitation of TPD is the scarcity of high-affinity ligands for most disease targets.
• Synthetic DNA offers a programmable and versatile platform to overcome this ligand gap.

Purpose of the Study:

• To present a comprehensive DNA molecular engineering framework to address challenges in TPD.
• To outline a systematic approach for ligand discovery, spatiotemporal control, and multifunctional integration in TPD systems.
• To enable the targeting of a broader range of proteins, including extracellular and membrane proteins.

Main Methods:

• Development of a four-tier DNA engineering framework for TPD.
• Utilizing phosphorothioate-modified aptamers for enhanced biostability and affinity.
• Integrating drug conjugates and alternative degradation pathways (e.g., autophagy) via covalent aptamer-based chimeras (CAPTEC).
• Incorporating endogenous and exogenous triggers for intelligent, on-demand regulation.
• Designing polyvalent nanoscale platforms (PANTAC) for membrane protein degradation.

Main Results:

• Demonstrated enhanced biostability and affinity of aptamers for compartment-selective degradation.
• Successfully integrated synergistic drug conjugates and hijacked autophagy.
• Achieved cell-selective activation and on-demand regulation using trigger elements.
• Developed a generalized method for membrane protein degradation via receptor-independent endocytosis.

Conclusions:

• The presented DNA engineering framework systematically overcomes key challenges in TPD, particularly ligand scarcity.
• This approach broadens the addressable proteome and advances programmable precision medicine.
• Rational design of DNA-based degraders facilitates precise protein manipulation and intelligent therapeutics.