Therapeutic m(6)A eraser ALKBH5 mRNA-loaded exosome-liposome hybrid nanoparticles inhibit progression of colorectal cancer in preclinical tumor models

Although therapeutic targets have been developed forcolorectalcancer (CRC) therapy, the therapeutic effects are not ideal and thesurvival rate for CRC patients remains poor. Therefore, it is crucialto recognize a specific target and develop an efficacious deliverysystem for CRC therapy. Herein, we demonstrate that reduced ALKBH5mediates aberrant m(6)A modification and tumor progressionin CRC. Mechanically, histone deacetylase 2-mediated H3K27 deacetylationinhibits ALKBH5 transcription in CRC, whereas ectopic ALKBH5 expressiondecreases tumorigenesis of CRC cells and protects mice from colitis-associatedtumor development. Further, METTL14/ALKBH5/IGF2BPs combine to modulateJMJD8 stability in an m(6)A-dependent manner, which increasesglycolysis and accelerates the development of CRC by enhancing theenzymatic activity of PKM2. Moreover, ALKBH5 mRNA-loaded folic acid-modifiedexosome-liposome hybrid nanoparticles were synthesized andsignificantly inhibit the progression of CRC in preclinical tumormodels by modulating the ALKBH5/JMJD8/PKM2 axis and inhibiting glycolysis.Overall, our research confirms the crucial function of ALKBH5 in regulatingthe m(6)A status in CRC and provides a direct preclinicalapproach for using ALKBH5 mRNA nanotherapeutics for CRC.