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Triple-Synergistic Therapy with Cobalt-Pheophytin Coordination Micelles for Overcoming Drug Resistance in Pancreatic

Zhen Jiang1, Yue Pan1, Gengqi Liu1

  • 1School of Synthetic Biology and Biomanufacturing, State Key Laboratory of Synthetic Biology, Frontiers Science Center for Synthetic Biology (Ministry of Education), Tianjin University, Tianjin 300350, P. R. China.

ACS Applied Bio Materials
|March 17, 2026
PubMed

Insights

This study introduces a novel cobalt-based micelle (CoPheo-ONC201-Pal-F127) to combat drug-resistant pancreatic cancer. It simultaneously triggers ferroptosis, disulfidptosis, and senescence, overcoming KRAS mutations.

Area of Science:

  • Biomedical Engineering
  • Nanotechnology
  • Oncology

Background:

  • Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with significant drug resistance due to KRAS mutations.
  • Targeting downstream signaling pathways is crucial for overcoming resistance in KRAS-mutant cancers.

Purpose of the Study:

  • To develop a novel drug delivery system for treating KRAS-mutant pancreatic cancer.
  • To overcome chemoresistance by simultaneously inducing multiple cell death pathways.

Main Methods:

  • Development of a cobalt-pheophytin coordination micelle (CoPheo-ONC201-Pal-F127) encapsulating ONC201 and Palbociclib.
  • Investigation of acid- and GSH-responsive drug release in the tumor microenvironment.
  • Evaluation of the micelle's ability to induce ferroptosis, disulfidptosis, and cellular senescence.

Main Results:

  • Cobalt's strong coordination enhanced drug loading and facilitated a Fenton-like reaction.
  • CoPheo-ONC201-Pal-F127 synergistically enhanced ONC201-induced AKT inhibition, amplifying ferroptosis.
  • The formulation disrupted redox homeostasis and induced disulfidptosis, while also promoting senescence via MEK and CDK4/6 inhibition.

Conclusions:

  • The CoPheo-ONC201-Pal-F127 micelle offers a multi-pronged therapeutic strategy against KRAS-mutant pancreatic cancer.
  • This approach effectively overcomes drug resistance by targeting three independent cell death pathways.
  • The study highlights the potential of metal-based coordination micelles in cancer therapy.
Keywords:
KRASSASPcobalt coordination micellesdisulfidptosisferroptosis

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