Fig. 3

EV-based TBI treatment strategies: Neuronal cells appeared degenerative and necrosis (a) and released PEV (b) after TBI; PEV further exacerbate nerve cell damage (a & c); The combination of PEV and VWF into a complex significantly increased the permeability of the BBB and further damaged the normal structure of the BBB (d), so PEV entered the peripheral circulation through the damaged BBB; PEV in the peripheral circulation activated platelets and caused them to release more EVs, while EVs trigger and propagate the coagulation cascade, leading to of thrombosis and ultimately coagulopathy (f); Meanwhile, PEV in the circulation activate immune cells to trigger an inflammatory response (e). Activated immune cells not only could enter the brain parenchyma through the damaged BBB (h) and exacerbate nerve cell damage (i) and PEV release (b), but also synergized with PEV to cause degeneration and necrosis of recipient cells (g), eventually causing systemic complications; In addition, persistent inflammation and nerve damage increased the risk of neurodegenerative diseases (a, b & c). There are two strategies for EV-based TBI treatment. First, the function of PEV is inhibited, for example, accelerating the clearance of PEV by lactadherin (j), inhibiting the procoagulant function of PEV by ANV-6L15 (k) and inhibiting the uptake of PEV by recipient cells by heparin (l). Second, BEV, such as immune cell/MSC-EV (m) can be increased or EEV can be infused (n), which will play an anti-inflammatory role and promote tissue repair. Meanwhile, BEV and EEV can also carry protective factors through the BBB to the brain parenchyma to play a protective role (o). In conclusion, EV-based TBI treatment strategies can effectively prevent nerve cell damage and PEV release (p); Furthermore, BEV and EEV can also repair damaged nerve cells and promote nerve regeneration (q). Abbreviations: ANV-6L15: ANV-6L15 fusion protein; BBB: blood–brain barrier; BEV: biological extracellular vesicles; EEV: engineered special purpose extracellular vesicles; EVs: extracellular vesicles; MSC: mesenchymal stromal cells; PEV: pathological extracellular vesicles; TBI: Traumatic brain injury; VWF: von Willebrand factor. Figure created with BioRender.com