A mitochondria-targeted supramolecular nanoplatform overcomes cisplatin resistance via self-amplified ferroptosis.

Authors

Ying Liu, Zongtao Zhou, Wei Ma, Cui-Yun Yu, Hua Wei

Published in

International journal of pharmaceutics. Pages 127444. Sep 18, 2026. Epub Sep 18, 2026.

Abstract

An upregulated GPX4 level of tumor cells with enhanced antioxidant defense systems accounts substantially for cisplatin resistance, but on the other hand, offers a unique therapeutic strategy due to the improved sensitivity of tumor cells to ferroptosis. Effective ferroptosis induction remains a challenge owing to insufficient intracellular ROS generation and limited catalytic iron availability. Herein, we report a mitochondria-targeted, ROS-activatable supramolecular delivery nanoplatform for self-amplifying redox imbalance and reversing cisplatin resistance. A multifunctional guest molecule, Fc-NTA-BBR, was rationally engineered by conjugating berberine (BBR) for mitochondrial targeting, thioacetal-based cinnamaldehyde (CA) derivative NTA for ROS generation, and ferrocene (Fc) for Fenton-like ferroptosis catalysis via a ROS-cleavable thioacetal link between Fc and BBR moieties. Meanwhile, a Pt(IV)-modified cyclodextrin (CD-Pt) was leveraged as the host component to serve as a glutathione-responsive cisplatin prodrug. Further CD/Fc host-guest complexation leads to the formation of an amphiphilic supramolecular construct between CD-Pt and Fc-NTA-BBR, affording stabilized nanoparticles with a hydrodynamic diameter of 157.4 nm. Upon cellular uptake, GSH triggers cisplatin release from Pt(IV), while Fc-NTA-BBR undergoes subcellular localization to the mitochondria wherein ROS cleaves the linker to release CA, BBR, and Fc. CA and BBR collectively amplifies ROS generation, whereas Fc catalyzes ROS-to-hydroxyl radical conversion and enables continuous Fenton catalysis via redox cycling. The resulting Fc-NTA-BBR/CD-Pt nanoparticles achieve 7.9-fold enhanced cytotoxicity (vs. cisplatin) in A549/DDP cells and 4.6-fold greater tumor suppression in A549/DDP-bearing mice without systemic toxicity due to the synergistic mitochondrial dysfunction and self-amplifying oxidative cascade. Overall, this work presents a supramolecular prodrug nanoplatform that harnesses GPX4-associated ferroptosis sensitivity for enhanced cisplatin-based cancer therapy.

PMID:
42759672
Bibliographic data and abstract were imported from PubMed on 19 Sep 2026.

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