Multifunctional nanolocks with GSH as the key for synergistic ferroptosis and anti-chemotherapeutic resistance

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Oncology

Background:

• Chemotherapeutic resistance, often linked to reactive oxygen species (ROS) imbalance and oxidative stress, is a major cause of anti-tumor therapy failure.
• Overcoming this resistance is crucial for improving cancer treatment outcomes.

Purpose of the Study:

• To develop a glutathione (GSH)-triggered ferroptosis and apoptosis integrated strategy to overcome mitoxantrone (MTO) resistance.
• To investigate the mechanism of reversing chemotherapeutic resistance by inducing ferroptosis in drug-resistant tumors.

Main Methods:

• Designed MTO-Cu(II)-cRGD nanolocks that dissociate in the tumor microenvironment due to overexpressed GSH, releasing Cu(I) and MTO.
• Utilized Cu(I) for Fenton-like reactions to generate hydroxyl radicals (•OH) and MTO for photothermal effects.
• Leveraged GSH depletion to inactivate GPX4, leading to lipid peroxide (LPO) accumulation and ferroptosis induction.
• Employed photoacoustic imaging for guidance.

Main Results:

• The nanolocks effectively released therapeutic agents and induced ferroptosis by depleting GSH and inactivating GPX4.
• The integrated strategy successfully prohibited mitoxantrone resistance by disrupting oxidative stress defenses.
• Solid tumors were eliminated through ferroptosis-sensitized chemotherapy.

Conclusions:

• The study presents a feasible strategy for treating drug-resistant tumors by reversing chemotherapeutic resistance through ferroptosis.
• The developed nanolock system demonstrates potential for effective anti-tumor therapy guided by photoacoustic imaging.