Split‐Deliver‐Click: Tumor‐Specific Protein Degradation via “AND” Logic‐Gated In‐Cell Bioorthogonal Clicking of PROTACs

ABSTRACT PROteolysis TArgeting Chimeras (PROTACs) represents a promising therapeutic modality with the potential to revolutionize targeted protein degradation. However, challenges such as low bioavailability and off‐target effects significantly limit their clinical efficacy. Herein, we introduce a Split‐Deliver‐Click nanoplatform that enables tumor‐specific protein degradation through “AND” logic‐gated, in‐cell bioorthogonal clicking of PROTACs, inspired by the ternary structure of PROTACs and logic‐gated stimulus‐sensitive drug delivery. First, PROTACs were split with click‐reactive ligands, enabling their direct use in cellular assays for efficient PROTAC screening. Next, a delivery system was developed, utilizing an “AND” logic gate mechanism triggered by tumor‐overexpressed enzymes legumain and cathepsin B to separately activate and release the split PROTAC precursors. Finally, this approach permitted in‐cell click chemistry to generate PROTAC (Click‐PROTAC), achieving efficient and specific protein degradation. This Split‐Deliver‐Click strategy facilitated the in situ generation of PROTACs for precise protein degradation.