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A biomimetic nanodrug self-assembled from small molecules for enhanced ferroptosis therapy
Xueming Xu1, Yuan Chen2, Jinyong Gui3
1School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, PR China.
Abstract:
Ferroptosis drugs often induce oxidative damage or block antioxidant defense due to the key mechanism of ferroptosis involved in cancer treatment, regulating the intracellular redox balance. However, these ferroptosis drugs are unstable during systemic circulation, and they lack tumor-targeting capability. Herein, we developed a stimuli-responsive and cell membrane-coated nanodrug for the simultaneous delivery of two ferroptosis drugs, an iron-chelating drug as a ROS inducer and sorafenib as an antioxidase inhibitor. The coating of the cancer cell membrane over the nanodrug can enhance the tumor-targeting capability and improve the stability in the blood circulation. In addition, the nanodrug exhibits sensitive drug release profiles in response to glutathione (GSH) and reactive oxygen species (ROS) in tumor microenvironments due to the dynamic diselenide bonds. The released iron-chelating drug and sorafenib not only produce hydroxyl radicals (˙OH) to induce ferroptosis, but also inhibit the expression of GPX4 to mitigate the ferroptosis resistance. Excitingly, the systemic administration of this biomimetic nanodrug displays superior antitumor and anti-metastatic effects in tumor-bearing mice. Our findings provide a promising therapeutic strategy for the co-delivery of ferroptosis inducers and antioxidase inhibitors to strengthen the therapeutic efficacy of ferroptosis.
Insights
This study presents a novel nanodrug that co-delivers ferroptosis-inducing and antioxidant-inhibiting drugs. This biomimetic nanodrug enhances tumor targeting and stability, showing potent antitumor and anti-metastatic effects.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Therapy
Background:
- Ferroptosis drugs regulate intracellular redox balance for cancer treatment but suffer from instability and lack of tumor targeting.
- Existing ferroptosis inducers can cause oxidative damage or block antioxidant defenses, complicating their therapeutic application.
Purpose of the Study:
- To develop a stimuli-responsive, cell membrane-coated nanodrug for simultaneous delivery of two ferroptosis-modulating agents.
- To enhance tumor targeting, improve systemic stability, and achieve targeted drug release in the tumor microenvironment.
Main Methods:
- Development of a nanodrug coated with cancer cell membrane for enhanced targeting and stability.
- Incorporation of an iron-chelating drug (ROS inducer) and sorafenib (antioxidase inhibitor) for synergistic ferroptosis induction.
- Utilizing dynamic diselenide bonds for stimuli-responsive drug release triggered by glutathione (GSH) and reactive oxygen species (ROS).
Main Results:
- The biomimetic nanodrug demonstrated enhanced tumor-targeting capability and improved stability during systemic circulation.
- The nanodrug effectively released both drugs in response to tumor microenvironment stimuli (GSH and ROS).
- Co-delivery of drugs induced ferroptosis by producing hydroxyl radicals and inhibiting GPX4, overcoming ferroptosis resistance.
- Systemic administration resulted in significant antitumor and anti-metastatic effects in preclinical tumor models.
Conclusions:
- The developed stimuli-responsive, cell membrane-coated nanodrug is a promising strategy for co-delivering ferroptosis inducers and antioxidase inhibitors.
- This approach significantly enhances therapeutic efficacy against tumors and metastasis by overcoming ferroptosis resistance.
- The findings offer a novel therapeutic avenue for improving ferroptosis-based cancer treatments.
