Heparan Sulfate-Based Neoproteoglycan for Targeted Lysosomal Degradation of Amyloid-β

Targeted lysosomal degradation of proteins (LDP) represents a promising strategy for clearing unwanted toxic extracellular and secreted proteins. Yet, significant challenges persist, including identifying potential ligands for these proteins and lysosome-driving probes capable of facilitating their internalization and degradation through receptor-mediated endocytosis. Herein, we show that synthetic neoproteoglycan probes stably anchor to the cell membrane, facilitate the internalization of amyloid-β (Aβ) peptide into the lysosomal compartment, and mediate the programmed death of Aβ. We have identified sulfated oligo l-idose tetrasaccharide (ID49) and heparan sulfate hexasaccharides (HH26S) as potential ligands for Aβ_1–42 peptide. When these molecules are expressed on the peptide-based fluorescent neoproteoglycan backbone, PG@HH26S persists on the cell membrane and facilitates Aβ_1–42 endocytosis to the lysosomal compartment and subsequent targeted degradation of Aβ_1–42. Overall, neoproteoglycans open a new avenue to generate LDP for degrading HS-binding proteins, including growth factors, morphogens, and toxic secreted proteins.