Iron Single Atom Nanozyme-Mediated GPX4 Inhibitor Delivery for Self-Enhanced Ferroptosis

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Cancer Therapy

Background:

• Ferroptosis, an iron-dependent cell death, is a promising cancer therapy target due to cancer cells' high iron and ROS levels.
• Single-atom nanozymes (SANs) can induce ferroptosis but are limited by glutathione and GPX4, which scavenge ROS and suppress lipid peroxidation (LPO).

Purpose of the Study:

• To engineer a novel Fe-based SAN (Fe-SAN) combined with a GPX4 inhibitor (Fin56) to overcome limitations in ferroptosis induction.
• To develop a synergistic nanoplatform (Fe-SAN@F) for enhanced ferroptosis and tumor suppression.

Main Methods:

• Fabrication of Fe-SAN with Fe-N4 active sites and encapsulation of Fin56 to create Fe-SAN@F.
• Evaluation of Fe-SAN@F's dual catalytic activities: peroxidase-like and glutathione oxidase-like.
• In vitro and in vivo assessment of Fe-SAN@F-induced ferroptosis and tumor suppression.

Main Results:

• Fe-SAN@F demonstrated robust peroxidase-like activity, generating cytotoxic hydroxyl radicals (•OH) to induce LPO.
• Fe-SAN@F exhibited glutathione oxidase-like activity, depleting intracellular GSH and inactivating GPX4.
• Combined with Fin56, Fe-SAN@F synergistically inhibited GPX4, amplified ROS, and induced irreversible ferroptosis, suppressing tumor growth.

Conclusions:

• The Fe-SAN@F nanoplatform effectively induces tumor ferroptosis through combined LPO accumulation, GSH depletion, and GPX4 inactivation.
• This work presents a novel SAN-based catalytic therapy for cancer, offering a new design strategy for precision antitumor nanozymes.
• The developed platform shows potential for remodeling the tumor microenvironment and enhancing ferroptosis-driven cancer treatment.