biostudies-literatureUnknown6(1)Peng TAptamer-based lysosome-targeting chimeras (Apt-LYTACs) have emerged as a promising strategy for the selective degradation of cell surface proteins by linking a target-specific aptamer to a lysosome-trafficking receptor ligand. However, their degradation efficiency is often limited by weak noncovalent interactions, heterogeneous receptor distribution, and the constraints of a 1:1 complex stoichiometry. To address these challenges, we developed aptamer-mediated covalent dual lysosome-targeting chimeras (Apt-cdLYTACs), which enable specific covalent anchoring to the protein of interest with spatiotemporal control by combining the specificity of aptamer recognition with proximity-induced photoreactive cross-linking. These chimeras incorporate two lysosomal receptor ligands to enhance the localJACS Au144-153https://www.ebi.ac.uk/biostudies/studies/S-EPMC12848693biostudies-literatureAptamer-Mediated Covalent Dual Lysosome-Targeting Chimeras Enhance Targeted Degradation of Cell Surface Proteins.PMC12848693Li JPeng TZhang ZZhu YSu MWang YfalseAptamer-Mediated Covalent Dual Lysosome-Targeting Chimeras Enhance Targeted Degradation of Cell Surface Proteins.Aptamer-based lysosome-targeting chimeras (Apt-LYTACs) have emerged as a promising strategy for the selective degradation of cell surface proteins by linking a target-specific aptamer to a lysosome-trafficking receptor ligand. However, their degradation efficiency is often limited by weak noncovalent interactions, heterogeneous receptor distribution, and the constraints of a 1:1 complex stoichiometry. To address these challenges, we developed aptamer-mediated covalent dual lysosome-targeting chimeras (Apt-cdLYTACs), which enable specific covalent anchoring to the protein of interest with spatiotemporal control by combining the specificity of aptamer recognition with proximity-induced photoreactive cross-linking. These chimeras incorporate two lysosomal receptor ligands to enhance the local2026-01-01T00:00:00Z2026 Jan2026-06-14T06:07:31.167Z2026-06-14T03:16:46.871ZS-EPMC128486934161417710.1021/jacsau.5c00978