Self-amplifying ROS-responsive trinity nanodelivery system for enhanced cancer therapy

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Cancer Therapy

Background:

• Ferroptosis is a promising antitumor strategy but faces challenges like toxicity and poor specificity.
• Existing ferroptosis inducers often target single pathways, limiting efficacy.

Purpose of the Study:

• To develop a novel reactive oxygen species (ROS)-responsive nanodelivery system for enhanced ferroptosis induction.
• To overcome limitations of conventional ferroptosis inducers through a multi-pronged approach.

Main Methods:

• Co-assembly of Ferrocenecarboxaldehyde (Fc-CHO) and RAS-selective lethal 3 (RSL3) into nanostructures with AA-PEG2k.
• Utilizing the tumor microenvironment to trigger ROS burst via Fenton reaction.
• ROS-mediated cleavage of AA-PEG2k to release RSL3, inhibiting GPX4 and supplying arachidonic acid (AA) for lipid peroxidation.

Main Results:

• The nanodelivery system achieved cascade amplification of ferroptosis.
• Demonstrated significant antitumor efficacy in vitro (tumor-on-a-chip) and in vivo animal studies.
• Successfully overcame ferroptosis resistance through integrated pathway regulation.

Conclusions:

• The developed trinity nanodelivery system offers a versatile strategy for precise ferroptosis induction.
• Provides a theoretical foundation for developing targeted nanomaterials in cancer therapy.
• Highlights the potential of multi-pathway targeting for overcoming drug resistance.