Hepatocyte-Targeted Cyclic Peptide LYTACs for PCSK9 Degradation and LDL Cholesterol Metabolic Regulation

Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes the degradation of the LDL receptor (LDLR), thereby increasing LDL cholesterol (LDL-C) levels and elevating the risk of cardiovascular disease. Current antibodies and siRNA target and inhibit secreted PCSK9 but are clinically costly, noncatalytic in action, and induce feedback upregulation. High-affinity cyclic peptides (<b>CP1</b>/<b>CP2</b>) developed by Merck and Novartis block the PCSK9-LDLR interaction but induce compensatory PCSK9 elevation. Herein, we report cyclic peptide-based lysosome-targeting chimeras (LYTACs), <b>LY1</b> and <b>LY2</b>, constructed by conjugating <b>CP1</b>/<b>CP2</b> with triantennary <i>N</i>-acetylgalactosamine (tri-GalNAc) for hepatocyte-specific ASGPR-mediated uptake and lysosomal degradation. In Huh7 cells, <b>LY1</b>/<b>LY2</b> reduced extracellular PCSK9 and restored LDL uptake, outperforming nondegradative <b>CP1</b>/<b>CP2</b>. Mechanistic studies confirmed the ASGPR-dependent endocytosis and lysosomal degradation. Notably, in hyperlipidemic mice, <b>LY1</b> treatment significantly depleted circulating PCSK9 and restored lipid profiles. These results demonstrate the robust therapeutic potential of our liver-targeted LYTAC platform for sustained plasma PCSK9 clearance and effective cholesterol regulation.