Histone Deacetylase‐Triggered Self‐Immolative Peptide‐Cytotoxins for Cancer‐Selective Drug Delivery

Abstract Precise delivery and release of therapeutics in the subcellular targets are critical for tumor‐selective chemotherapy. Self‐immolative structures are sophisticatedly designed to achieve stimuli‐responsive drug delivery. Herein, the facile fabrication of self‐immolative peptide‐camptothecin (CPT) nanoassemblies is reported for cancer‐selective drug delivery by utilizing the dual‐mode peptide targeting design and amine‐catalyzed intramolecular hydrolysis. The dual‐mode peptide targeting design is realized by co‐assembly of tumor targeting and nuclei‐localizing peptide‐CPT prodrugs, rendering the nanoassemblies with efficient cancer cell‐selective capability. When the nanoassemblies enter cancer cell, the overexpressed endonuclear histone deacetylases (HDACs) cleave the acetyl group to generate primary amines, triggers amine‐catalyzed intramolecular hydrolysis, and fast‐release drug in the cell nuclei. The peptide‐CPT prodrugs release up to 68% CPT in 1 h in the presence of HDACs, while no detectable CPT release is observed in the absence of HDACs at the same time. The peptide‐CPT prodrugs selectively kill cancer cells with high HDACs levels. The dual targeting peptide‐CPT nanoassemblies exhibit extended blood circulation, excellent tumor accumulation, and potent antitumor activity by inhibiting tumor progression and metastasis in mice bearing 4T1 aggressive breast tumors. Overall, the HDAC‐triggered self‐immolative strategy is promising for developing cancer‐selective drug delivery systems.