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

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.