This study was published in Bioactive under the title "Bioengineered extracellular vesicles escape lysosomal degradation and deliver Tet-PKM2 for macrophage immunometabolic reprogramming and periodontitis treatment." Materials. The study pointed out that regulating macrophage phenotypes and functions through immunometabolic reprogramming represents a new therapeutic paradigm for combating chronic inflammatory diseases such as periodontitis. Tetraisomeric pyruvate kinase M2 (Tet-PKM2) is a highly active metabolic enzyme involved in the flow of glucose source carbon to tricarboxylic acids (TCA) and oxidative phosphorylation (OXPHOS). It is significantly reduced during inflammatory responses and has become a potential immunometabolic target for developing new therapies. Therefore, this study reports a large extracellular vesicle (LEV) bioengineered for intracellular delivery of Tet-PKM2, reprogramming pro-inflammatory macrophages and restoring their abnormal immune metabolism. Researchers designed tannic acid-modified Tet-PKM2-enriched LEVs (LEVsTet−PKM2@TA) capable of intracellular delivery of Tet-PKM2 and enhancing its ability to evade lysosomal degradation, thereby enabling intracellular delivery of Tet-PKM2. In vitro experiments, LEVsTet−PKM2@TA successfully salvaged lipopolysaccharide (LPS) activation of abnormal pyruvate metabolism in macrophages by enhancing TCA cycling activity and enhancing mitochondrial OXPHOS metabolism. In vivo, LEVsTet−PKM2@TA exerts powerful immunomodulatory effects by enhancing pyruvate kinase (PK) activity and guiding macrophages toward the M2 phenotype, ultimately achieving robust periodontal tissue regeneration in a mouse sterilization-induced periodontitis model. This study offers a versatile and safe approach to targeted delivery of Tet-PKM2 via EVs to regulate macrophage phenotype and function, demonstrating a new concept for immunometabolic reprogramming in the treatment of chronic inflammatory diseases.