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Updated: May 21, 2025
Polymalic Acid-based Nano Biopolymers for Targeting of Multiple Tumor Markers: An Opportunity for Personalized Medicine?
Published on: June 13, 2014
Programable Prodrug Nanomodulator Targets Tumor Redox Homeostasis Imbalance to Amplify Disulfidptosis and Immunogenic
Ayeskanta Mohanty1, Adityanarayan Mohapatra1,2, Woojin Yang3
1Department of Biomedical Sciences and BioMedical Sciences Graduate Program (BMSGP), Chonnam National University Medical School, Gwangju, 61469, Republic of Korea.
Abstract:
Despite the great potential of photodynamic therapy (PDT), its success remains compromised by the abnormal redox homeostasis of tumor cells, which supports survival, growth, and resistance to oxidative therapeutic interventions by neutralizing reactive oxygen species (ROS). To overcome this barrier, a multifunctional prodrug nanomodulator (Pro@FLNC) is designed to induce disulfidptosis and immunogenic pyroptosis to trigger an antitumor immune response. Pro@FLNC features a prodrug core-shell structure where ursolic acid (UA) and Chlorin e6 (Ce6) are conjugated via a GSH-responsive linker and encapsulated in a DSPE-PEG-FA lipid shell for enhanced stability, biocompatibility, and tumor-specific targeting. Within the tumor microenvironment (TME), Pro@FLNC depletes intracellular GSH, disrupts redox homeostasis, and releases Ce6 and UA, triggering oxidative stress and mitochondrial dysfunction. These mechanisms amplify ROS production, promote lipid peroxidation, and initiate disulfidptosis, evidenced by increased SLC7A11 expression and F-actin collapse. Elevated ROS levels and metabolic imbalance-triggered disulfidptosis further activate immunogenic pyroptosis, releasing damage-associated molecular patterns (DAMPs) that stimulate dendritic cell maturation and cytotoxic T-cell activation. Together, Pro@FLNC reshapes the TME, reduces immunosuppressive cells, and promotes CD8+ T-cell infiltration, effectively suppressing primary tumors and metastases. This programmed prodrug nanomodulator offers a promising strategy to enhance PDT and immunotherapy for advanced breast cancer.
Insights
This study introduces a novel nanomodulator that combats cancer by inducing programmed cell death pathways, enhancing the immune response against tumors. It effectively targets cancer cells, promoting therapeutic outcomes in preclinical models.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Therapy
Background:
- Tumor cells possess abnormal redox homeostasis, hindering photodynamic therapy (PDT) by neutralizing reactive oxygen species (ROS).
- This redox imbalance promotes cancer cell survival, growth, and resistance to oxidative treatments.
Purpose of the Study:
- To develop a multifunctional prodrug nanomodulator (Pro@FLNC) to overcome redox homeostasis in tumors.
- To induce disulfidptosis and immunogenic pyroptosis for a potent antitumor immune response.
Main Methods:
- Pro@FLNC utilizes a core-shell structure with ursolic acid (UA) and Chlorin e6 (Ce6) linked by a GSH-responsive bond, encapsulated in a DSPE-PEG-FA lipid shell.
- The nanomodulator targets tumors, depletes glutathione (GSH), disrupts redox balance, and releases UA and Ce6 to induce oxidative stress.
Main Results:
- Pro@FLNC triggers disulfidptosis via increased SLC7A11 expression and F-actin collapse, amplifying ROS production and mitochondrial dysfunction.
- Disruptions in redox and metabolism activate immunogenic pyroptosis, releasing DAMPs that mature dendritic cells and activate cytotoxic T-cells.
- The treatment reshaped the tumor microenvironment, reduced immunosuppressive cells, and increased CD8+ T-cell infiltration, suppressing primary tumors and metastases.
Conclusions:
- The programmed prodrug nanomodulator Pro@FLNC effectively enhances PDT and immunotherapy.
- This strategy shows promise for treating advanced breast cancer by overcoming tumor redox homeostasis and stimulating antitumor immunity.
