Abstract

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 (CP1/CP2) 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), LY1 and LY2, constructed by conjugating CP1/CP2 with triantennary N-acetylgalactosamine (tri-GalNAc) for hepatocyte-specific ASGPR-mediated uptake and lysosomal degradation. In Huh7 cells, LY1/LY2 reduced extracellular PCSK9 and restored LDL uptake, outperforming nondegradative CP1/CP2. Mechanistic studies confirmed the ASGPR-dependent endocytosis and lysosomal degradation. Notably, in hyperlipidemic mice, LY1 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.