There are many extracellular neuroproteins of therapeutic interest including tau, amyloid beta and neuroinflammatory markers. A major hurdle for targeting these molecules and treating neurological diseases is the presence of the blood-brain barrier (BBB). The BBB is comprised of capillary endothelial cells connected by tight junctions which prevent the passive diffusion of hydrophilic and high molecular weight molecules across the membrane. These molecules require transport proteins, receptor-mediated transcytosis, or adsorptive--mediated transcytosis to access the brain. To overcome this barrier, brain-targeting peptides capable of facilitating receptor-mediated transcytosis have been utilized. The brain targeting peptide Angiopep-2 is a 19-amino acid peptide derived from the Kunitz proteinase inhibitor (KPI) domain of aprotinin. The KPI domain is a common feature of ligands for the low-density lipoprotein receptor gene family and binding results in endocytosis and lysosomal degradation of the KPI containing protein. Angiopep-2 mediated transcytosis has been hypothesized to occur via ligation of the endocytic receptor low-density lipoprotein receptor related protein 1 (LRP1). Angiopep-2 has been utilized as a covalent tag to redirect therapeutics to the brain for the treatment of glioma. Clinical studies showed that Angiopep-2 is generally well tolerated. Currently, Angiopep-2-based technologies show preclinical success in the delivery of a variety of therapeutics, including small molecule chemotherapeutics, antibodies, and nanoparticles. Herein, we present a proof-of-concept study showing that MoDEs consisting of Angiopep-2 modified to include a small molecule ligand are capable of inducing target internalization in a variety of cell types. Upon endocytosis, target protein is removed by both transcytosis and lysosomal degradation (Figure ). Notably these effects are not believed to be mediated through LRP-1.