HMGB1 and metabolic dysfunction-associated steatotic liver disease: 2019; Biessels et al. 2020), our findings indicate that EVs provide broad systemic benefits to the db/db brain. Considering the vulnerability of the hippocampus (Johnson 2023; Biessels and Reagan 2015), markers of hippocampal damage, including S100β (neuronal and astrocytic damage), Aqp4 (brain oedema and BBB dysfunction), and HMGB1 (cell damage marker), were significantly reduced in db/db mice following EV infusion (Figure 2N–Q), further supporting the potent neuroprotective effects of EVs in T2DM with NAFLD.