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Assembly of Glycopeptides in Living Cells Resembling Viral Infection for Cargo Delivery.

Abstract
Self-assembly in living cells represents one versatile strategy for drug delivery; however, it suffers from the limited precision and efficiency. Inspired by viral traits, we here report a cascade targeting-hydrolysis-transformation (THT) assembly of glycosylated peptides in living cells holistically resembling viral infection for efficient cargo delivery and combined tumor therapy. We design a glycosylated peptide via incorporating a β-galactose-serine residue into bola-amphiphilic sequences. Co-assembling of the glycosylated peptide with two counterparts containing irinotecan (IRI) or ligand TSFAEYWNLLSP (PMI) results in formation of the glycosylated co-assemblies SgVEIP, which target cancer cells via β-galactose-galectin-1 association and undergo galactosidase-induced morphological transformation. While GSH-reduction causes release of IRI from the co-assemblies, the PMI moieties release p53 and facilitate cell death via binding with protein MDM2. Cellular experiments show membrane targeting, endo-/lysosome-mediated internalization and in situ formation of nanofibers in cytoplasm by SgVEIP. This cascade THT process enables efficient delivery of IRI and PMI into cancer cells secreting Gal-1 and overexpressing β-galactosidase. In vivo studies illustrate enhanced tumor accumulation and retention of the glycosylated co-assemblies, thereby suppressing tumor growth. Our findings demonstrate an in situ assembly strategy mimicking viral infection, thus providing a new route for drug delivery and cancer therapy in the future.
AuthorsFeng Tian, Ruo-Chen Guo, Chunxia Wu, Xin Liu, Zeyu Zhang, Yamei Wang, Hao Wang, Gongyu Li, Zhilin Yu
JournalAngewandte Chemie (International ed. in English) (Angew Chem Int Ed Engl) Pg. e202404703 (Apr 24 2024) ISSN: 1521-3773 [Electronic] Germany
PMID38655625 (Publication Type: Journal Article)
Copyright© 2024 Wiley‐VCH GmbH.

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