2. Academic Validation
  3. Enzyme-instructed disassembly of phosphorylated temporin supramolecules enhances doxorubicin synergy for targeted cancer inhibition

Enzyme-instructed disassembly of phosphorylated temporin supramolecules enhances doxorubicin synergy for targeted cancer inhibition

  • J Control Release. 2025 Aug 29:387:114176. doi: 10.1016/j.jconrel.2025.114176.
Tingting Li 1,  Yixuan Lin 2,  Binwen Yuan 1,  Huilei Dong 3,  Mingshui Wang 1,  Dan Yuan 4,  Tingting Tang 5,  Junfeng Shi 6
Affiliations

Affiliations

  • 1 Hunan Provincial Key Laboratory of Animal Models and Molecular Medicine, State Key Laboratory of Chemo/Bio-Sensing and Chemometrics, School of Biomedical Sciences, Hunan University, Changsha 410082, China.
  • 2 Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200125, China.
  • 3 Hunan Provincial Key Laboratory of Animal Models and Molecular Medicine, State Key Laboratory of Chemo/Bio-Sensing and Chemometrics, School of Biomedical Sciences, Hunan University, Changsha 410082, China; School of Pharmacy, Jiangxi Medical College, Nanchang University, Nanchang 330031, China.
  • 4 Hunan Provincial Key Laboratory of Animal Models and Molecular Medicine, State Key Laboratory of Chemo/Bio-Sensing and Chemometrics, School of Biomedical Sciences, Hunan University, Changsha 410082, China. Electronic address: yuandan@hnu.edu.cn.
  • 5 Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200125, China. Electronic address: ttt@sjtu.edu.cn.
  • 6 Hunan Provincial Key Laboratory of Animal Models and Molecular Medicine, State Key Laboratory of Chemo/Bio-Sensing and Chemometrics, School of Biomedical Sciences, Hunan University, Changsha 410082, China; Shenzhen Research Institute, Hunan University, Shenzhen 518000, Guangdong Province, China. Electronic address: jeff-shi@hnu.edu.cn.
PMID: 40886776 DOI: 10.1016/j.jconrel.2025.114176
Abstract

Enzyme-instructed self-assembly has emerged as a powerful tool to engineer selective functional Materials. However, its reverse process, enzyme-instructed disassembly, has been largely overlooked despite its critical implications in pharmaceutical research. This study introduces a new approach employing enzyme-instructed peptide disassembly to selectively inhibit Cancer cells. Specifically, a phosphorylated random coil peptide TLP self-assembles into non-ordered inert aggregates under physiological conditions. Upon enzymatic dephosphorylation on Cancer cell membranes (e.g., Saos-2), these assemblies dissociate into bioactive α-helical monomers TL, exhibiting an 8.9 folds selectivity towards Cancer cells over normal cells. This cascade involves phosphate cleavage-induced supramolecular disassembly, conformational switching to membrane-penetrating helices, and selective cytotoxicity towards high ALP-expressing cells. Notably, enzymatic dephosphorylation alters TLP's isoelectric point (pI) from 7.35 to 9.06, establishing a pI-driven design principle for supramolecular phase control. In orthotopic osteosarcoma models, TLP synergizes with doxorubicin exhibited doubling efficacy while reducing toxicity. This EIDA strategy not only enhances chemotherapy selectivity but also underscores disassembly as a crucial yet underutilized tool in drug development.

Keywords

ALP-instructed disassembly; Cell selectivity; Conformational change; cancer inhibition.

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