# Copper-Based Targeted Nanocatalytic Therapeutics for Non-Small Cell Lung Cancer

## TL;DR

Researchers developed copper-based nanoparticles that target lung cancer cells and kill them by generating reactive oxygen species, offering a promising new treatment approach.

## Contribution

A novel hyaluronic acid-modified copper-based nanocatalyst that induces ferroptosis in non-small cell lung cancer cells.

## Key findings

- Cu-DMSA-HA NPs selectively target CD44 receptors on cancer cells and generate ROS via coordination chemistry.
- The NPs induce mitochondrial disruption, GSH depletion, and GPX4 downregulation, leading to ferroptosis in NSCLC cells.
- In vitro and in vivo studies show effective inhibition of NSCLC progression with minimal off-target effects.

## Abstract

Developed a novel type of nanoparticles (NPs)—hyaluronic acid (HA)-modified copper-N,N-dimethyl-N-phenylsulfonylbisamine (DMSA)-assembled NPs (Cu-DMSA-HA NPs).The constructed NPs were surface-modified with HA to selectively target overexpressed cluster of differentiation 44 (CD44) receptors on cancer cells and catalytically generate highly efficient reactive oxygen species (ROS) via coordination chemistry.Such efficient ROS generation induced intracellular ROS accumulation, mitochondrial disruption, glutathione (GSH) depletion, and glutathione peroxidase 4 (GPX4) downregulation, ultimately triggering ferroptosis in cancer cells.

Developed a novel type of nanoparticles (NPs)—hyaluronic acid (HA)-modified copper-N,N-dimethyl-N-phenylsulfonylbisamine (DMSA)-assembled NPs (Cu-DMSA-HA NPs).

The constructed NPs were surface-modified with HA to selectively target overexpressed cluster of differentiation 44 (CD44) receptors on cancer cells and catalytically generate highly efficient reactive oxygen species (ROS) via coordination chemistry.

Such efficient ROS generation induced intracellular ROS accumulation, mitochondrial disruption, glutathione (GSH) depletion, and glutathione peroxidase 4 (GPX4) downregulation, ultimately triggering ferroptosis in cancer cells.

The online version contains supplementary material available at 10.1007/s40820-025-01998-5.

Conventional treatments for non-small cell lung cancer (NSCLC) suffer from low remission rates, high drug resistance, and severe adverse effects. To leverage the therapeutic potential of reactive oxygen species (ROS), nanocatalytic medicine utilizes nanomaterials to generate ROS specifically within tumor sites, enabling efficient and targeted cancer treatment. In this study, hyaluronic acid (HA)-modified copper-N,N-dimethyl-N-phenylsulfonylbisamine (DMSA)-assembled nanoparticles (Cu-DMSA-HA NPs) are developed with tumor-targeting capability and efficiently catalyze ROS production via coordination chemistry. Targeted delivery is facilitated by HA surface modification through recognition of overexpressed cluster of differentiation 44 receptors on cancer cells, which enhances nanoparticle uptake. Once internalized, intracellular glutathione is depleted by the NPs, followed by a Fenton-like reaction that sustains ROS production. Both in vitro and in vivo studies demonstrate that this catalytic strategy effectively inhibits DNA replication, prevents cell cycle progression, downregulates glutathione peroxidase 4 expression, induces ferroptosis, and ultimately suppresses NSCLC progression. Overall, the readily prepared Cu-DMSA-HA NPs exhibit robust catalytic activity and tumor specificity, highlighting their strong potential for clinical translation in nanocatalytic cancer therapy.

The online version contains supplementary material available at 10.1007/s40820-025-01998-5.