Key Takeaways & Executive Findings
- •• Developed novel hyaluronic acid-modified copper-DMSA nanoparticles (Cu-DMSA-HA NPs) for targeted NSCLC therapy. • HA surface modification enables selective targeting of CD44-overexpressing cancer cells, enhancing uptake and specificity. • NPs deplete glutathione and sustain ROS production via Fenton-like reaction, inducing ferroptosis and suppressing tumor growth. • In vitro and in vivo results demonstrate robust catalytic activity and tumor specificity, highlighting clinical translation potential.
Abstract
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, down-regulates 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.
1. Introduction
Lung cancer remains the leading cause of cancer-related morbidity and mortality worldwide, with an estimated 1.8 million deaths (18.7%) each year [1]. Among all subtypes, non-small cell lung cancer (NSCLC) accounts for a predominant proportion, approximately 80%–85% of all cases, and presents significant clinical challenges [1, 2]. A major challenge is that surgical resection is primarily effective for early-stage NSCLC patients, while treatment options for advanced-stage NSCLC patients largely rely on chemotherapeutic agents (e.g., cisplatin, paclitaxel, pemetrexed) and immunotherapeutic agents (e.g., pembrolizumab, nivolumab) [3–5]. However, these drugs often have limitations; for instance, chemotherapy drugs are frequently associated with a low remission rate, high drug resistance, and severe adverse effects (SAEs); immunotherapy drugs are usually accompanied by poor pathological response rates, which largely restricts their clinical effectiveness [6–8]. Therefore, developing novel therapeutic strategies is essential to improve clinical outcomes for patients with advanced-stage NSCLC.
Recent advances in materials science and nanotechnology have inspired novel therapeutic strategies by leveraging catalytic and redox-based mechanisms—such as piezocatalysis, nanocatalysis, and metal (e.g., copper)-mediated cell death, to address unmet clinical challenges [9–12]. Specifically, radiotherapy and several chemotherapeutic agents exert their therapeutic effects, in part, through the generation of reactive oxygen species (ROS) within tumor tissues, leading to oxidative damage and cell death [13–16]. Inspired by these clinical principles, nanocatalytic medicine has emerged as a promising strategy that employs nanoparticles (NPs) to initiate site-specific chemical reactions directly within the tumor microenvironment (TME), resulting in localized ROS production and enhanced therapeutic effects in situ. This approach not only of
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Yongfei Fan, Jiao Chang, Xichun Qin, Meng Li, Yan Li, Leilei Wu, Kun Li, Zhimin Chen, Yani Li, Zhongmin Tang, Dong Xie, Jianlin Shi (2026). Copper-Based Targeted Nanocatalytic Therapeutics for Non-Small Cell Lung Cancer. Nano-Micro Letters. https://doi.org/10.1007/s40820-025-01998-5
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Frequently Asked Questions
What is the main innovation of this study?
The study develops hyaluronic acid-modified copper-DMSA nanoparticles (Cu-DMSA-HA NPs) that selectively target CD44-overexpressing NSCLC cells and generate reactive oxygen species via a Fenton-like reaction, inducing ferroptosis and suppressing tumor growth.
How do Cu-DMSA-HA NPs achieve tumor targeting?
The nanoparticles are surface-modified with hyaluronic acid, which specifically binds to CD44 receptors overexpressed on cancer cells, enhancing cellular uptake and tumor specificity.
What is the mechanism of action of Cu-DMSA-HA NPs?
Once internalized, the NPs deplete intracellular glutathione, followed by a Fenton-like reaction that sustains ROS production. This leads to mitochondrial disruption, GPX4 downregulation, and ultimately ferroptosis in cancer cells.
What are the potential clinical implications?
The Cu-DMSA-HA NPs exhibit robust catalytic activity and tumor specificity, suggesting strong potential for clinical translation in nanocatalytic cancer therapy, particularly for advanced NSCLC.
What is the significance of using copper in this therapy?
Copper-based nanoparticles can catalyze Fenton-like reactions to generate ROS, and copper is also involved in cuproptosis, a newly discovered cell death pathway, offering a dual mechanism for cancer treatment.
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