Targeted degradation of membrane proteins would afford an attractive and general strategy for treating various diseases that remain difficult with the current PROTAC methodology. We herein report a covalent nanobody-based PROTAC strategy, termed GlueTAC, for targeted membrane protein degradation with high specificity and efficiency. We first designed a MS-based screening platform for rapid development of covalent nanobody (Gluebody) that allowed proximity-enabled ligation with surface antigens on cancer cells. By conjugation with the cell-penetrating peptide and lysosomal-sorting sequence, the resulting GlueTAC chimera exhibited enhanced internalization with high efficacy and sustained eradication of tumor surface antigens such as PD-L1 and EGFR both in vitro and in vivo, which has broad applications in biomedical research and therapeutics.