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Therapeutic m6A Eraser ALKBH5 mRNA-Loaded Exosome-Liposome Hybrid Nanoparticles Inhibit Progression of Colorectal
Shenshen Wu1, Jun Yun2, Weiyan Tang3
1School of Public Health, Capital Medical University, Beijing 100069, China.
Abstract:
Although therapeutic targets have been developed for colorectal cancer (CRC) therapy, the therapeutic effects are not ideal and the survival rate for CRC patients remains poor. Therefore, it is crucial to recognize a specific target and develop an efficacious delivery system for CRC therapy. Herein, we demonstrate that reduced ALKBH5 mediates aberrant m6A modification and tumor progression in CRC. Mechanically, histone deacetylase 2-mediated H3K27 deacetylation inhibits ALKBH5 transcription in CRC, whereas ectopic ALKBH5 expression decreases tumorigenesis of CRC cells and protects mice from colitis-associated tumor development. Further, METTL14/ALKBH5/IGF2BPs combine to modulate JMJD8 stability in an m6A-dependent manner, which increases glycolysis and accelerates the development of CRC by enhancing the enzymatic activity of PKM2. Moreover, ALKBH5 mRNA-loaded folic acid-modified exosome-liposome hybrid nanoparticles were synthesized and significantly inhibit the progression of CRC in preclinical tumor models by modulating the ALKBH5/JMJD8/PKM2 axis and inhibiting glycolysis. Overall, our research confirms the crucial function of ALKBH5 in regulating the m6A status in CRC and provides a direct preclinical approach for using ALKBH5 mRNA nanotherapeutics for CRC.
Insights
Reduced ALKBH5 levels drive colorectal cancer (CRC) progression through aberrant m6A modification. ALKBH5 mRNA nanotherapeutics show promise in preclinical models for CRC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Nanomedicine
Background:
- Colorectal cancer (CRC) therapy faces challenges with suboptimal outcomes.
- Identifying novel therapeutic targets and effective delivery systems for CRC is crucial.
Purpose of the Study:
- To investigate the role of ALKBH5 in colorectal cancer (CRC) progression.
- To develop and evaluate an ALKBH5 mRNA-based nanotherapeutic for CRC treatment.
Main Methods:
- Investigated the mechanism of ALKBH5 regulation by histone deacetylase 2.
- Assessed the impact of ALKBH5 expression on CRC cell tumorigenesis and tumor development in mice.
- Synthesized and tested ALKBH5 mRNA-loaded folic acid-modified exosome-liposome hybrid nanoparticles in preclinical CRC models.
Main Results:
- Reduced ALKBH5 expression was found to mediate aberrant m6A modification and promote CRC progression.
- Ectopic ALKBH5 expression inhibited CRC cell tumorigenesis and protected against tumor development.
- The METTL14/ALKBH5/IGF2BPs complex modulates JMJD8 stability, increasing glycolysis and CRC development via PKM2.
- ALKBH5 mRNA nanotherapeutics significantly inhibited CRC progression in preclinical models by targeting the ALKBH5/JMJD8/PKM2 axis and glycolysis.
Conclusions:
- ALKBH5 plays a critical role in regulating m6A modification in colorectal cancer.
- ALKBH5 mRNA nanotherapeutics represent a promising preclinical approach for CRC treatment.
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