Aptamer–Based Targeted Protein Degradation: Mechanistic Principles, Delivery Strategies, and Translational Opportunities

ABSTRACT Targeted elimination of pathogenic proteins remains a fundamental challenge in therapeutic intervention, particularly for proteins considered “undruggable” by conventional inhibition‐based approaches. Aptamer–based targeted protein degradation (TPD) has emerged as a versatile strategy that leverages the high specificity, structural programmability, and chemical tunability of nucleic acid aptamers to redirect disease‐relevant proteins toward endogenous degradation pathways. Intracellular platforms, exemplified by aptamer‐conjugated proteolysis‐targeting chimeras (PROTACs), induce ubiquitination and proteasomal degradation of cytosolic and nuclear targets. In parallel, extracellular and membrane‐targeting modalities, including aptamer‐conjugated lysosome‐targeting chimeras (LYTACs) and related lysosomal degradation systems, enable clearance of secreted and membrane‐bound proteins that are inaccessible to proteasome‐based strategies. Collectively, these approaches broaden the potentially degradable proteome and offer opportunities to improve target selectivity and therapeutic safety. However, most aptamer‐based TPD systems remain at the proof‐of‐concept or early preclinical stage, with limited standardization of degradation potency, kinetics, selectivity, and in vivo efficacy. Additional challenges include the discovery of functionally active aptamers, preservation of affinity and activity after chemical modification or conjugation, efficient delivery, chemical stability, controlled biodistribution, and mitigation of innate immune activation. This review provides a mechanistic and comparative framework for intracellular and extracellular aptamer‐based TPD strategies, with emphasis on quantitative performance, delivery considerations, technical bottlenecks, and their translational potential for precision protein‐targeted therapeutics.