The coordinated activity of macrophages is essential for bone repair, with pro-inflammatory M1 macrophages driving early responses and anti-inflammatory M2 macrophages supporting later tissue remodeling. While both phenotypes are required, prolonged persistence of either subtype can impair healing, underscoring the correct transition between the two states. Macrophage polarization is closely linked to cellular metabolism, and human macrophages display distinct metabolic profiles. Macrophage-derived extracellular vesicles (EVs) carry bioactive cargo and reflect parental polarization, influencing recipient cell function. This raises critical questions about how metabolic regulation influences human macrophage function, their EVs and their effect on angiogenesis and osteogenesis. This study investigates EVs derived from polarized primary human macrophages and from macrophages exposed to DASA-58, a small molecule which activates the metabolic enzyme pyruvate kinase M2 (PKM2). Alterations in macrophage metabolism modifies the molecular cargo of their EVs, including microRNAs (miRNAs), to modulate regenerative activity. These findings demonstrate that human macrophage-derived EVs exert metabolically dependent effects on angiogenesis and osteogenesis, and that metabolic modulation enables the generation of EVs with hybrid pro-regenerative properties intermediate between M1 and M2. This establishes metabolic reprogramming within human macrophages using small molecules as a strategy to engineer novel phenotypes and EVs for bone repair. • EVs M1 promote MSC migration and early ALP activity; EVs M2 enhance angiogenesis. • DASA-58 reprograms M1 macrophages into a hybrid M1/M2 state with dual functions. • DASA-58-induced EVs promote angiogenesis while preserving osteogenic potential. • Hybrid EVs share M1/M2 miRNA cargo,enhancing regenerative and therapeutic effects.
Görgün et al. (Wed,) studied this question.