Inhibition of METTL3 protect against traumatic brain injury

Researchers recently identified STM2457 as a first-in-class catalytic inhibitor of METTL3 and observed a promising therapeutic effect on acute myeloid leukemia. However, it is crucial to note that the existence of the blood-brain barrier (BBB) limit the efficiency of drugs entering the brain to a large extent. In order to effectively deliver METTL3 inhibitor STM2457 to the brain, we generated RVG29 (a BBB-penetrating peptide)-based modified nanoparticle system loaded with STM2457 (abbreviated as RVG-nSTM system) that targets the brain. Specifically, a mixture of STM2457, PLGA20K-mPEG2K, and PLGA20K-PEG5K-MAL was used to prepare nSTM, which was further modified with RVG29 peptide. We investigated the impact of RVG-nSTM on neuroinflammation post-TBI in mice. We performed a total RNA-seq analysis, and observed distinct gene distributions on the volcano plot. A Venn diagram revealed that 3385 genes were differentially expressed in the TBI group compared to the sham group, and treatment with RVG-nSTM reversed the expression of 1941 of these genes . The subsequent GO and KEGG analyses showed that these 1941 genes were primarily enriched in the context of inflammatory response and inflammation-related pathways. These findings were further corroborated by the observation that RVG-nSTM treatment leads to a substantial reversal of the hyperactive microglial states that are induced by TBI . Above all, RVG-nSTM could be a promising agent for the treatment of neuroinflammation after acute brain injury.