2026-10-10T20:25:08Z https://api.figshare.com/v2/oai

oai:figshare.com:article/32641962 2026-10-01T16:19:20Z portal_1172 item_type_8 month_year_10_2026

A serum-stable antimicrobial peptide-based delivery platform for selective treatment of non-targetable and chemo-resistant tumours Tianxing Liu (10938882) PUREID: 659408975 Antimicrobial peptide (AMP)-based therapeutic system membrane affinity reconstruction small-molecule ligands conformation-driven PEGylated blocker N-terminal cap serum stability cytotoxicity untargetable and drug-resistant cancers Antibody–drug conjugates have transformed cancer therapy but remain limited by their dependence on internalizing antigens, poor applicability to untargetable tumours, and susceptibility to drug resistance. Therefore, a modular antimicrobial peptide (AMP)-based therapeutic system, conjugate 270, was presented, which integrates three optimized components: a selectivity-enhanced AMP core via a membrane affinity reconstruction strategy, a conformation-driven PEGylated blocker to minimize off-target effects, and an N-terminal cap to improve stability in human serum. By targeting non-endocytic membrane surface receptors via small-molecule ligands, conjugate 270 exhibited potent and selective cytotoxicity against target tumour cells, effectively eliminating the majority of tumour cells within a few hours. Meanwhile, it exhibited high serum stability, minimal haemolysis, and negligible cytotoxicity toward normal cells at therapeutic concentrations. Mechanistic studies confirmed ligand-dependent membrane localization, rapid depolarization and disruption, along with mitochondrial dysfunction. Moreover, it demonstrated significant therapeutic efficacy against four cell lines resistant to conventional chemotherapeutic agents. While additional in vivo validation is warranted, this work lays the foundation for a flexible AMP-based approach to address conventional untargetable and drug-resistant cancers.<br><br><i>Thesis is embargoed until 31 December 2030.</i> 2026-10-01T16:19:20Z Text Thesis 10.17034/32641962.v1 https://figshare.com/articles/thesis/A_serum-stable_antimicrobial_peptide-based_delivery_platform_for_selective_treatment_of_non-targetable_and_chemo-resistant_tumours/32641962 All Rights Reserved Open Access after 2030-12-31