Drugs that mediate active degradation of their protein target are currently one of the most actively investigated areas in medicinal chemistry. Indeed, chimeric small molecule drugs (PROteolysis Targeting Chimeras, or PROTACs) have been invented that link up the target protein to an ubiquitin E3 ligase for subsequent proteasomal degradation, ablating all of the functions of the target protein. However, such strategies have been limited to targets within the intracellular environment, accessible to the proteasome. Here, we introduce a novel biopharmaceutical concept to direct extracellular target proteins for degradation in the lysosome. We make use of unique VHH single-domain antibodies that we developed, directed against the cation-independent mannose-6-phosphate receptor (CI-M6PR). This constitutively endocytosing receptor targets its protein ligands to the lysosome. This is widely used for enzyme replacement therapy of lysosomal storage diseases. Now, by fusing these lysosome-targeting VHHs to other VHHs that bind to extracellularly accessible disease target proteins, we target these for lysosomal degradation. We named this concept ‘Nanobody-based Lysosome-Targeting Chimeras’ (nanoLYTACs) and will test it in two settings. First, we will target receptor tyrosine kinases that frequently drive cancer, with EGFR as a benchmark testcase. Second, we will use our center’s recently generated VHHs against conserved epitopes on SARS-CoV-2 and influenza membrane proteins.