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

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.