In Vivo Self‐Assembly of PROTACs by Bioorthogonal Chemistry for Precision Cancer Therapy

Abstract Proteolysis targeting chimeras (PROTACs) hold immense promise for targeted protein degradation; however, challenges such as off‐target effects, poor drug‐likeness properties, and the “hook effect” remain. This study introduces Nano‐Click‐formed PROTACs (Nano‐CLIPTACs) for precise tumor protein degradation in vivo. Traditional PROTACs with high molecular weight were first divided into two smaller druglike precursors capable of self‐assembling to form functional PROTACs through a bioorthogonal reaction. Then, optimal CLIPTACs precursors ( W4 and Z2 ) were encapsulated individually into cyclic RGDfC‐peptide‐modified liposomes to prepare Nano‐CLIPTACs, enabling tumor‐targeted delivery and subsequent in situ self‐assembly to form PROTACs WZ42 within tumor cells. The degradation abilities of Nano‐CLIPTACs in vitro and in vivo were further verified using a key oncology target, anaplastic lymphoma kinase (ALK), validating the safety, efficacy and “anti‐hook effect” of this strategy. Overall, Nano‐CLIPTACs represent a critical step towards the clinical translation of PROTACs technology for precise targeted anti‐cancer therapies.