<i>In Vivo</i> Self‐Assembly of PROTACs by Bioorthogonal Chemistry for Precision Cancer Therapy

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.