PROTACs (proteolysis targeting chimeras) are bivalent molecules composed of a ligand binding to a target protein, linked via a spacer to another ligand binding to a ubiquitin E3 ligase. Contrary to the traditional inhibition-based protein inhibition, PROTACs could reprogram the ubiquitin-proteasome system to execute protein degradation. Recent research demonstrated that PROTACs mediated protein degradation could display superior therapeutic efficacies, such as lower dosage, longer effect and higher specificity compared to the traditional protein inhibition. However, issues such as low binding affinity and hook effect are major bottlenecks for the further development of PROTACs. In this application, we proposed a new concept that we term ‘m/mPROTAC’ (macromolecular multivalent proteolysis targeting chimeras). m/mPROTACs, composed of multiple ligands of target protein and E3 ligase, could dramatically increase their binding affinity to the target protein and E3 ligase, therefore further facilitate the crucial ternary complex formation and target protein degradation. Besides that, due to the nature of multivalence, m/mPROTACs could sever as a promising design to circumvent the hook effect. We anticipate that our m/mPROTACs technology could be another breakthrough in PROTACs development.