Ulcerative colitis (UC) is a chronic inflammatory bowel disease mainly involving the colon and rectum, which features recurrent mucosal inflammation. The excessive production of reactive oxygen species (ROS) is a trigger for pathological changes such as cell apoptosis and disordered immune microenvironments, which are crucial for the progression of UC and can be a promising therapeutic target. Nowadays, the development of targeted therapeutic strategies for UC is still in its infancy. Thus, developing effective therapies based on ROS scavenging and elucidating their molecular pathways are urgently needed. Herein, a biomimetic nanoformulation (Pd@M) with cubic palladium (Pd) as the core and macrophage‐derived extracellular vesicles (MEVs) as the shell is synthesized for the treatment of UC. These Pd@M nanoformulations exhibit multienzyme‐like activities for effective ROS scavenging, excellent targeting ability as well as good biocompatibility. It is verified that Pd@M can regulate the polarization state of macrophages by inhibiting glycolysis, and decrease neutrophil infiltration and recruitment. In this way, the colonic inflammatory and immune microenvironment is remodeled, and apoptosis is prevented, ultimately improving colonic mucosal barrier function and alleviating colitis in the mouse model. This finding provides a promising alternative option for the treatment of UC patients.

BACKGROUND: Senescent foamy macrophages are key drivers of atherosclerosis and plaque instability. N ⁶ -methyladenosine (m ⁶ A) modification of RNA plays an important role in the development of various diseases including aging. Here, we aim to investigate the role of m ⁶ A modification of RNA in the formation of senescent foamy macrophages in atherosclerosis. METHODS: To assess m ⁶ A methylation, macrophages were isolated from the atherosclerotic plaques of patients with atherosclerosis, and Apoe ^−/− mice were fed a high-fat diet using flow cytometry. An ALKBH5 (alkB homolog 5) ^f/f , Lyz2 (lysozyme 2) ^Cre , Apoe ^−/− mouse model was generated to determine the infiltration of senescent foamy macrophages into plaques and atherosclerosis progression. Methylated RNA immunoprecipitation, RNA immunoprecipitation sequencing, and dual-luciferase assays were performed to explore the mechanisms underlying the ALKBH5-mediated formation of senescent foamy macrophages. RESULTS: Decreased m ⁶ A methylation and increased ALKBH5 expression were observed in arterial plaques and infiltrating macrophages from patients and mice with atherosclerosis. Compared with control mice, ALKBH5 ^f/f , Lyz2 ^Cre , Apoe ^−/− mice exhibited fewer atherosclerosis plaques with greater stability, which was attributed to the suppression of senescent foamy macrophage formation and senescence-associated secretory phenotype. In addition, ALKBH5 deletion reduced the mRNA expression level of CCL5 (CC chemokine ligand 5) by increasing m ⁶ A methylation in macrophages, which disrupts the stability of CCL5 mRNA. Mechanistically, ALKBH5 promoted senescent foamy macrophage formation through the CCL5/CCR5 (CC chemokine receptor 5)/autophagy signaling pathway. CCL5 also recruited CD8 ⁺ IFN (interferon)γ ⁺ T cells via the CCL5-CCR5 axis. The ALKBH5 inhibitor IOX1 (inhibitor of 2OG oxygenases) and the CCR5 antagonist maraviroc were identified as potential clinical interventions for inhibiting senescent foamy macrophage formation and atherosclerosis progression. CONCLUSIONS: Myeloid ALKBH5 deletion attenuates atherosclerosis progression by suppressing the formation of senescent foamy macrophages and the recruitment of CD8 ⁺ IFNγ ⁺ T cells. These findings identify ALKBH5, CCL5, and CCR5 as novel therapeutic targets for atherosclerosis.