PCSK9-LYTAC

PCSK9 is a key regulator of LDLR turnover and an established therapeutic target for CVD. Here, we report the development of a bispecific DNA aptamer-based lysosome-targeting chimera (PCSK9-LYTAC) that promotes extracellular degradation of PCSK9 via IGFIIR-mediated lysosomal trafficking. This dual-aptamer construct simultaneously blocks the PCSK9-LDLR interaction and directs PCSK9 toward lysosomal degradation. In HepG2 cells, PCSK9-LYTAC efficiently undergoes lysosomal localization and significantly restores LDL uptake (∼22% recovery), outperforming the corresponding monovalent PCSK9 aptamer. Mechanistically, this functional rescue is associated with enhanced LDLR availability at the cell surface following PCSK9 degradation. Collectively, these results demonstrate the feasibility of aptamer-based LYTACs as a non-antibody, modular strategy for regulating extracellular protein homeostasis and highlight their potential for therapeutic intervention in dyslipidemia and CVD.