# Copper/iron-based intelligent nanoparticles self-amplify apoptosis/ferroptosis/cuproptosis in colorectal cancer

## TL;DR

This study introduces a new nanoparticle treatment that enhances colorectal cancer therapy by triggering multiple cell death pathways simultaneously.

## Contribution

A novel multi-pathway synergistic killing strategy using copper/iron-based nanoparticles to activate apoptosis, ferroptosis, and cuproptosis.

## Key findings

- CRDT@FC nanoparticles effectively kill colorectal cancer cells.
- The treatment induces apoptosis, ferroptosis, and cuproptosis in cancer cells.
- The strategy shows potential as a new modality for colorectal cancer treatment.

## Abstract

To address the key challenge of insufficient chemosensitivity in colorectal cancer treatment due to apoptosis resistance, this study proposes a “multi-pathway synergistic killing” strategy that enhances anti-tumour efficacy by simultaneously activating multiple cell death pathways, including apoptosis, ferroptosis, and cuproptosis. Utilising a cRGD targeting peptide, ferrocenecarboxylic acid (Fc), camptothecin (CPT), and doxorubicin (DOX), four amphiphilic molecules were designed and synthesised, which were further assembled and chelated with copper ions to construct multifunctional nanoparticles, cRDT@FC. These nanoparticles can efficiently accumulate in tumour regions. The disulphide bonds and Cu2+ within them jointly consume the high concentration of glutathione (GSH) in cells, leading to the disintegration of the nanostructure and the release of CPT, thereby achieving the desired chemotherapy effects. Meanwhile, Cu2+ is reduced by GSH to Cu+, which, in synergy with Fe2+ in the system, catalyses the Fenton reaction to generate a large amount of hydroxyl radicals (·OH) achieving chemodynamic therapy (CDT), significantly enhancing the oxidative stress level and thereby synergistically inducing ferroptosis and cuproptosis. This study presents a novel approach to developing multi-mode cell death synergistic treatment strategies utilising nanotechnology.

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•CRDT@FC effectively kills colorectal cancer cells.•CRDT@FC induces apoptosis, ferroptosis and cuproptosis in cancer cells.•CRDT@FC is a potential new modality for colorectal cancer treatment.

CRDT@FC effectively kills colorectal cancer cells.

CRDT@FC induces apoptosis, ferroptosis and cuproptosis in cancer cells.

CRDT@FC is a potential new modality for colorectal cancer treatment.