Engineering Semicarbazide‐Bearing Polypeptide Conjugates for Efficient Tumor Chemotherapy and Imaging of Tumor Metastasis

Abstract Polypeptide materials offer scalability, biocompatibility, and biodegradability, rendering them an ideal platform for biomedical applications. However, the preparation of polypeptides with specific functional groups, such as semicarbazide moieties, remains challenging. This work reports, for the first time, the straightforward synthesis of well‐defined methoxy‐terminated poly(ethylene glycol)‐ b ‐polypeptide hybrid block copolymers (HBCPs) containing semicarbazide moieties. This synthesis involves implementing the direct polymerization of environment‐stable N ‐phenoxycarbonyl‐functionalized α‐amino acid (NPCA) precursors, thereby avoiding the handling of labile N ‐carboxyanhydride (NCA) monomers. The resulting HBCPs containing semicarbazide moieties enable facile functionalization with aldehyde/ketone derivatives, forming pH‐cleavable semicarbazone linkages for tailored drug release. Particularly, the intracellular pH‐triggered hydrolysis of semicarbazone moieties restores the initial semicarbazide residues, facilitating endo‐lysosomal escape and thus improving therapeutic outcomes. Furthermore, the integration of the hypoxic probe ( Ir(btpna)(bpy) 2 ) into the pH‐responsive nanomedicines allows sequential responses to acidic and hypoxic tumor microenvironments, enabling precise detection of metastatic tumors. The innovative approach for designing bespoke functional polypeptides holds promise for advanced drug delivery and precision therapeutics.