Targeting astrocytic Dp71 attenuates BBB disruption after traumatic brain injury through WTAP-associated m⁶A regulation of MMP2.

Abstract

Blood-brain barrier (BBB) disruption is a major pathological feature of traumatic brain injury (TBI) that contributes to secondary damage and poor neurological recovery. Although astrocytes are essential for BBB homeostasis, the molecular basis of astrocyte-associated BBB dysfunction after TBI remains unclear. Here, we found that astrocytic dystrophin protein 71 (Dp71) expression was reduced after TBI in both patients and mouse models. In mice, further experimental down-regulation of astrocytic Dp71 attenuated secondary BBB disruption and was accompanied by reduced astrocyte activation, inflammatory cell infiltration, and matrix metalloproteinase-2 (MMP2) release. Mechanistically, nuclear Dp71 interacted with Wilms tumor 1-associated protein (WTAP) and influenced its ubiquitination, leading to changes in the N⁶-methyladenosine (m⁶A) modification, RNA stability, and expression of <i>MMP2</i> messenger RNA. In addition, biomimetic nanovesicles coated with astrocyte membranes enabled targeted delivery of small interfering RNA targeting Dp71 (siDp71) to astrocytes and reduced MMP2 release and BBB damage after TBI, suggesting a potential therapeutic strategy for mitigating BBB injury after TBI.