As much as 85% of the human proteome is considered to be undruggable as many proteins lack well-defined pockets for small-molecule drugs to bind and modulate their function. This has been challenged with the emergence of targeted protein degradation approaches, that make use of the cytosolic waste disposal system for the removal of a disease-causing protein, ablating all of its functions. However, such strategies have been limited to target engagement within the intracellular environment. We propose here a novel platform that couples a newly developed VHH directed against the cation-independent mannose-6-phosphate receptor (CI-M6PR) which triggers lysosomal uptake to a VHH that binds an extracellularly-accessible protein of interest, to target this protein for lysosomal degradation. Our technology, which we named Nanobody-based Lysosome-Targeting Chimeras (nanoLYTACs), will be tested in the context of two human diseases. One the one hand, we will produce nanoLYTACs targeting the human epidermal growth factor (EGFR), which is frequently overexpressed in colorectal cancer. We suggest that nanoLYTAC-mediated degradation of EGFR could lead to a potent anti-tumor effect, both in vitro and in vivo, above and beyond what can be achieved with the current anti-EGFR therapeutic antibodies. On the other hand, we will create nanoLYTACs that target conserved domains of the influenza A hemagglutinin or the matrix 2 protein, with the good of developing broadly protective anti-viral agents.