MoDE Design and Synthesis. We selected Angiopep-2 for its brain targeting capability as demonstrated through conjugation with small molecules, proteins, and nanoparticles. The application of Angiopep-2 for the delivery of paclitaxel involved attachment of three small molecule chemotherapeutics at the N-terminus, and  amines of Lysine-10 and Lysine-15, (R1.R2.R3) (Figure , Supp. Figure ) suggesting that these locations tolerate modification and conjugation does not interfere with receptor binding. We envisioned a divergent synthetic route that would enable modification at each of these three amines independently. This divergent strategy was achieved through the synthesis of, a common MoDE precursor consisting of Angiopep-2 with orthogonal protecting groups at each of the three amines: fluorenylmethyloxycarbonyl (Fmoc), 4-methyltrityl (Mtt) and allyloxycarbonyl (Alloc). Subsequently, these amines could each be deprotected chemoselectively to allow for site-specific incorporation of protein-targeting ligands at R1.R2.R3 (Table , Figure ). HaloTag is a haloalkane dehalogenase that forms a covalent bond with its chloroalkane ligand. MoDE 2 was synthesized, consisting of an Angiopep-2 peptide functionalized with a chloroalkane at position R3, and acetyl groups at R1 and R2 (Table , Supp. Fig. ). The capability of MoDE 2 to induce uptake of fluorescently labeled soluble recombinant HaloTag protein into mouse brain endothelial cell line, bEnd.3, was assessed using flow cytometry (Supp. Fig. ). BEnd.3 monolayers are widely used as a cell culture model of the BBB. MoDE concentration dependent increase in cell-associated fluorescence demonstrated MoDE-mediated uptake of the HaloTag target protein at 6h. This Angiopep-2-mediated transport of a covalently bound cargo is consistent with literature reports. Noncovalent streptavidin uptake in mouse brain cell lines. To the best of our knowledge, all previous applications of Angiopep-2 involved covalent conjugation of Angiopep-2 to the protein target. We hypothesized that an Angiopep-2 functionalized with a noncovalent ligand for a target protein would enable targeting of endogenous proteins for degradation.