Bispecific self-assembled peptides as supra-growth factors for preventing endotheliopathy and improving survival of traumatic brain injury in mice

Traumatic brain injury (TBI) causes endothelial injury (endotheliopathy), which contributes to a cascade of adverse events, including cerebral hemorrhage, edema and acute lung injury (ALI), and leads to poor clinical outcomes. Protecting endothelial integrity and targeting cerebral endothelium is therefore critical for preventing secondary cerebral injuries from TBI. However, effective treatment strategies in the clinic remain lacking. Here, we report a nanofiber of bispecific self-assembled peptide (BsSA) as a supra-growth factor that possesses multiple functions, such as binding to the blood‒brain barrier (BBB) and dual growth factor activity. BsSA protects TBI mice by binding to the BBB through Insulin-like growth factor 1 receptor (IGF-1R) and insulin receptor (IR) and ameliorating endothelial injury by activating the IGF-1R/IR signaling pathway. Specifically, this protection is achieved by promoting endothelial cell proliferation and survival and mitigating oxidative stress. Exogenous BsSA, as a therapeutic agent, prevented mice with TBI from developing brain and pulmonary endotheliopathy and improved their outcomes. This study identified BsSA as a potential therapeutic agent to reduce TBI-induced endotheliopathy, brain edema, and lung injury and improve TBI outcomes.