Molecular Engineering of Functional DNA Molecules toward Targeted Protein Degradation

ConspectusPrecise manipulation of the cellular proteome is a central challenge in biomedicine. Targeted protein degradation (TPD) has emerged as a transformative therapeutic strategy, capable of directly eliminating disease-causing proteins beyond the reach of traditional inhibition. However, its broad application is fundamentally constrained by the severe scarcity of high-affinity, cell-permeable ligands for most disease-relevant proteins. To bridge this critical ligand gap, synthetic DNA has been engineered to create a programmable, multifunctional core material for designing degraders. DNA's inherent biocompatibility, precise molecular programmability, and versatile functionalization render it an exceptionally flexible substrate for constructing sophisticated degradation systems.In this Account, we present a comprehensive DNA molecular engineering framework, organized into four sequential tiers, designed to systematically overcome the core challenges in the TPD field: ligand discovery, spatiotemporal precision, multifunctional integration, and the targeting of extracellular and membrane proteins. This framework outlines a logical evolution of capabilities. The first tier establishes the phosphorothioate-modified aptamers as programmable targeting modules with enhanced biostability and affinity, enabling compartment-selective degradation of nucleocytoplasmic shuttling proteins. The second tier expands the DNA scaffold into a multifunctional therapeutic chassis, integrating synergistic drug conjugates (ApTCs-3X) and hijacking alternative degradation pathways like autophagy based on covalent aptamer-based chimeras (CAPTEC). The third tier introduces intelligent control, incorporating both endogenous and exogenous trigger elements (e.g., microRNA, light) to achieve cell-selective activation and on-demand regulation. The final tier leverages DNA aptamers to architect polyvalent nanoscale platforms (PANTAC), facilitating the generalized degradation of membrane proteins via clathrin-mediated endocytosis in a receptor-independent manner. Collectively, this integrated framework charts a rational path from molecular recognition to intelligent therapeutic platforms, significantly broadening the addressable proteome and advancing the frontier of programmable precision medicine. We hope this Account offers insights into the rational design of programmable DNA-based degraders for overcoming ligand scarcity and achieving precise protein manipulation in living systems. We believe that the continuing advances in DNA molecular engineering, together with the expansion of druggable target space, would accelerate the transition toward intelligent, cell-specific therapeutics and advance the frontier of programmable precision medicine.