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Ultra-small Janus nanoparticle-induced activation of ferroptosis for synergistic tumor immunotherapy
Junrong Wang1, Zhifang Wang1, Lei Li1
1Institute of Frontier Chemistry, School of Chemistry and Chemical Engineering, Shandong University, Qingdao, Shandong 266237, PR China.
Abstract:
Ferroptosis induced by lipid peroxide (LPO) accumulation is an effective cell death pathway for cancer therapy. However, how to effectively induce ferroptosis at tumor sites and improve its therapeutic effectiveness remains challenging. Here, MnFe2O4@NaGdF4@NLG919@HA (MGNH) nanocomplex with tumor-specific targeting and TME response is constructed to overcome immunosuppressive tumor microenvironment (TME) to potentiate the curative effect of ferroptosis by coupling the immune checkpoint indoleamine 2,3-dioxygenase (IDO) inhibitor, NLG919, and hyaluronic acid (HA) to novel ultra-small MnFe2O4@NaGdF4 (MG) nanoparticles with a Janus structure. Firstly, tumor site-precise delivery of MG and NLG919 is achieved with HA targeting. Secondly, MG acts as a magnetic resonance imaging contrast agent, which not only has a good photothermal effect to realize tumor photothermal therapy, but also depletes glutathione and catalyzes the production of reactive oxygen species from endogenous H2O2, which effectively promotes the accumulation of LPO and inhibits the expression of glutathione peroxidase 4, achieving enhanced ferroptosis. Thirdly, NLG919 inhibits the differentiation of Tregs by blocking the tryptophan/kynurenine immune escape pathway, thereby reversing immunosuppressive TME together with the Mn2+-activated cGAS-STING pathway. This work contributes new perspectives for the development of novel ultra-small Janus nanoparticles to reshape immunosuppressive TME and ferroptosis activation. STATEMENT OF SIGNIFICANCE: The Janus structured MnFe2O4@NaGdF4@NLG919@HA (MGNH) nanocomplex was synthesized, which can realize the precise delivery of T1/T2 contrast agents MnFe2O4@NaGdF4 (MG) and NLG919 at the tumor site under the ultra-small Janus structural characteristics and targeted molecule HA. The production of ROS, consumption of GSH, and photothermal properties of MGNH make it possible for CDT/PTT activated ferroptosis, and synergistically disrupt and reprogram tumor growth and immunosuppressive tumor microenvironment with NLG919 and Mn2+-mediated activation of cGAS-STING pathway, achieving CDT/PTT/immunotherapy activated by ferroptosis. Meanwhile, ultra-small structural properties of MGNH facilitate subsequent metabolic clearance by the body, allowing for the minimization of potential biotoxicity associated with its prolonged retention.
Insights
This study developed a novel Janus-structured nanocomplex (MGNH) for cancer therapy. MGNH precisely targets tumors, induces ferroptosis, and reprograms the immunosuppressive tumor microenvironment, enhancing therapeutic outcomes.
Area of Science:
- Nanotechnology and Materials Science
- Cancer Therapy and Nanomedicine
- Immunology and Tumor Microenvironment Modulation
Background:
- Ferroptosis, induced by lipid peroxide accumulation, is a promising cancer therapy strategy.
- Challenges remain in effectively inducing ferroptosis at tumor sites and overcoming the immunosuppressive tumor microenvironment (TME).
- Developing targeted delivery systems that respond to the TME is crucial for enhancing cancer treatment efficacy.
Purpose of the Study:
- To construct a novel ultra-small Janus-structured nanocomplex (MGNH) for targeted cancer therapy.
- To potentiate ferroptosis-induced cancer cell death by overcoming TME-mediated immunosuppression.
- To integrate magnetic resonance imaging (MRI) contrast, photothermal therapy (PTT), and immunotherapy.
Main Methods:
- Synthesis of MnFe2O4@NaGdF4@NLG919@HA (MGNH) nanocomplex with Janus structure.
- Utilized hyaluronic acid (HA) for tumor-specific targeting and delivery of MG and NLG919.
- MG nanoparticles acted as MRI contrast agents, PTT agents, and catalysts for reactive oxygen species (ROS) production, promoting ferroptosis.
- NLG919 (IDO inhibitor) blocked the tryptophan/kynurenine pathway to reverse TME immunosuppression, activating the cGAS-STING pathway via Mn2+.
Main Results:
- MGNH achieved precise delivery of therapeutic agents to the tumor site.
- MGNH effectively induced ferroptosis through ROS generation, glutathione depletion, and inhibition of glutathione peroxidase 4.
- Combined PTT and ferroptosis induction synergistically disrupted tumor growth.
- NLG919 and Mn2+-mediated cGAS-STING pathway activation reprogrammed the immunosuppressive TME.
- The ultra-small size of MGNH facilitated metabolic clearance, minimizing potential biotoxicity.
Conclusions:
- The Janus-structured MGNH nanocomplex offers a novel platform for TME-responsive, targeted cancer therapy.
- MGNH synergistically combines ferroptosis induction, PTT, and immunotherapy for enhanced anti-tumor effects.
- This approach provides new strategies for developing advanced nanomedicines to combat cancer and reshape the tumor microenvironment.
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