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Updated: Jul 8, 2025
Polymalic Acid-based Nano Biopolymers for Targeting of Multiple Tumor Markers: An Opportunity for Personalized Medicine?
Published on: June 13, 2014
Site-specific controlled-release nanoparticles for immune reprogramming via dual metabolic inhibition against
Wenyan She1, Haimei Li1, Zichen Wang1
1College of Chemistry and Molecular Science, Wuhan University, Wuhan 430072, PR China.
Abstract:
Metabolic heterogeneity and the tumor immunosuppressive microenvironment (TIME) of triple-negative breast cancer (TNBC) hinder therapeutic effectiveness. Although emerging metabolic therapy and immunotherapy show promise, they are limited by off-target effects and immune escape. Here, a redox-activatable, sequentially-releasing nanoparticle (AMANC@M) for tumor-targeted delivery of anticancer agents and CRISPR/Cas9 has been developed. AMANC@M can reverse the TIME through dual metabolic inhibition, thereby enhancing TNBC therapy. AMANC@M demonstrates excellent biosafety and targets tumors precisely through biomimetic hybrid membrane-mediated homologous homing and the enhanced permeability and retention (EPR) effect. Once internalized into tumor cells, the CRISPR/Cas9 system ("energy nanolock") is released through glutathione (GSH) cleavage and effectively knocks down the expression of lactate dehydrogenase A (LDHA) to suppress glycolysis. After peeling off of the gene editing shell, a newly synthesized targeted drug, CPI-Z2 ("nutrihijacker" and "energy nanolock"), is released in a controlled manner to block the mitochondrial tricarboxylic acid (TCA) cycle. Nitric oxide (NO) produced from loaded L-arginine enhances the efficiency of CPI-Z2 and reduces drug resistance. Combined with NO therapy, both blockades of nutrients and energy production transform the hypoxia and acidic TIME into an immunocompetent tumor microenvironment (TME) for tumor elimination. Furthermore, AMANC@M offers capabilities for photothermal (PT) therapy and provides clear imaging through PT, photoacoustic (PA), or computed tomography (CT) signals in tumor tissue. Thus, this study provides a new and promising sequentially stimuli-responsive targeting strategy for nanoparticle development, making it a potential treatment candidate for TNBC and other tumors.
Insights
This study developed a novel nanoparticle (AMANC@M) that targets triple-negative breast cancer (TNBC) by inhibiting tumor metabolism and reversing the immunosuppressive tumor microenvironment (TIME), enhancing therapeutic outcomes.
Area of Science:
- Biomedical Engineering
- Nanomedicine
- Cancer Therapy
Background:
- Metabolic heterogeneity and the immunosuppressive tumor microenvironment (TIME) limit triple-negative breast cancer (TNBC) treatment effectiveness.
- Existing metabolic therapies and immunotherapies face challenges with off-target effects and immune escape.
Purpose of the Study:
- To develop a redox-activatable, sequentially-releasing nanoparticle (AMANC@M) for targeted delivery of anticancer agents and CRISPR/Cas9 to TNBC.
- To reverse the TIME via dual metabolic inhibition and enhance TNBC therapy.
- To investigate the potential of AMANC@M for photothermal therapy and imaging.
Main Methods:
- Designed AMANC@M with a biomimetic hybrid membrane for tumor targeting via homologous homing and the EPR effect.
- Utilized CRISPR/Cas9 released by glutathione (GSH) to downregulate lactate dehydrogenase A (LDHA) and inhibit glycolysis.
- Sequentially released CPI-Z2 to block the mitochondrial tricarboxylic acid (TCA) cycle, with nitric oxide (NO) enhancing drug efficacy and reducing resistance.
Main Results:
- AMANC@M demonstrated precise tumor targeting and excellent biosafety.
- Dual metabolic blockade (glycolysis and TCA cycle) and NO therapy successfully transformed the TIME into an immunocompetent TME.
- The nanoparticle enabled photothermal therapy and provided multimodal imaging (PT, PA, CT).
Conclusions:
- AMANC@M represents a promising strategy for sequential, stimuli-responsive, targeted nanoparticle delivery.
- This approach effectively enhances TNBC therapy by reprogramming the tumor microenvironment.
- AMANC@M shows potential as a therapeutic candidate for TNBC and other cancers.
