<p>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 () and heparan sulfate hexasaccharides () as potential ligands for Aβ peptide. When these molecules are expressed on the peptide-based fluorescent neoproteoglycan backbone, persists on the cell membrane and facilitates Aβ endocytosis to the lysosomal compartment and subsequent targeted degradation of Aβ. Overall, neoproteoglycans open a new avenue to generate LDP for degrading HS-binding proteins, including growth factors, morphogens, and toxic secreted proteins.</p>
