Meningeal lymphatics restoration and neurovascular protection synergistically improve traumatic brain injury treatment.

• Meningeal lymphatics hyperplasia but drainage decrease in open-skull TBI mouse model. • An GelMA-vECM hydrogel with sustained co-delivery of VEGF-C 156S and EVs for TBI. • This hydrogel enhanced lymphatic drainage and provided neurovascular protection for TBI. • The motor function was improved following TBI after this novel invasive treatment. Persistent neuroinflammation following traumatic brain injury (TBI) remains to be a significant challenge in the clinic, however, the role of meningeal lymphatics dysfunction related to neuroinflammation has been largely ignored in TBI pathogenesis. We found meningeal lymphatics exhibited hyperplasia but the lymphatic drainage was decreased in moderate open-skull TBI. Besides, surgical ligation of the efferent lymphatic exacerbated the microglia responses and deteriorated motor function. To tackle this problem, here we designed neuroinflammation-resolving hydrogel to enhance lymphatic drainage and provide a protective effect for neurovascular. Specifically, VEGF-C 156S and bone mesenchymal stem cells derived extracellular vehicles (EVs) loaded injectable gelatin-methacryloyl (GelMA) hydrogel delivery system is constructed for these bioactive components continuous release. Such delivery system not only promotes functional meningeal lymphangiogenesis and increases lymphatic drainage, but also provides neurovascular protection and reduces microglia activation. Moreover, VEGF-C 156S works synergistically with EVs in decreasing microglia activation, neuron loss, as well as promoting angiogenesis to enhance motor function. Overall, rejuvenation lymphatic drainage provides neurovascular protection for neurological function improvement could be a novel strategy for TBI treatment. [ABSTRACT FROM AUTHOR]