biostudies-literatureUnknown5(12)Ma YDespite significant progress in extracellular targeted protein degradation (eTPD), existing approaches rarely achieved tissue-specific drug accumulation while maintaining efficient systemic clearance, a critical challenge in treating bone disorders. In this study, we introduced GalNAc-Apc001, a novel aptamer-based lysosome-targeting chimera (LYTAC) that uniquely combined bone-specific retention with hepatocyte-mediated clearance through a spatiotemporally controlled mechanism. By conjugating a tri-N-acetylgalactosamine (GalNAc) moiety to a bone-homing sclerostin aptamer (Apc001), we engineered a bifunctional molecule capable of accumulating in bone via hydroxyapatite binding, capturing circulating sclerostin with high affinity and directing it to hepatocytes for ASGPR-mediated lysosomal deJACS Au5973-5984https://www.ebi.ac.uk/biostudies/studies/S-EPMC12728634biostudies-literatureHarnessing Bone-Liver Crosstalk: A Dual-Action LYTAC Approach for Bone-Specific Accumulation and Liver-Specific Protein Degradation in Bone Disorders.PMC12728634Zhang GPan YYu SZhong CJiang HZhang HMa YLuo HLu AWang LYang XChen ZZhang YAmu GTao XZhang BYu YfalseHarnessing Bone-Liver Crosstalk: A Dual-Action LYTAC Approach for Bone-Specific Accumulation and Liver-Specific Protein Degradation in Bone Disorders.Despite significant progress in extracellular targeted protein degradation (eTPD), existing approaches rarely achieved tissue-specific drug accumulation while maintaining efficient systemic clearance, a critical challenge in treating bone disorders. In this study, we introduced GalNAc-Apc001, a novel aptamer-based lysosome-targeting chimera (LYTAC) that uniquely combined bone-specific retention with hepatocyte-mediated clearance through a spatiotemporally controlled mechanism. By conjugating a tri-N-acetylgalactosamine (GalNAc) moiety to a bone-homing sclerostin aptamer (Apc001), we engineered a bifunctional molecule capable of accumulating in bone via hydroxyapatite binding, capturing circulating sclerostin with high affinity and directing it to hepatocytes for ASGPR-mediated lysosomal de2025-01-01T00:00:00Z2025 Dec2026-06-06T05:45:20.293Z2026-05-26T03:12:29.959ZS-EPMC127286344145066210.1021/jacsau.5c00827