Sex-Dependent Macromolecule and Nanoparticle Delivery in Experimental Brain Injury

The development of effective therapeutics for brain disorders is challenging, in particular, the blood-brain barrier (BBB) severely limits access of the therapeutics into the brain parenchyma. Traumatic brain injury (TBI) may lead to transient BBB permeability that affords a unique opportunity for therapeutic delivery via intravenous administration ranging from macromolecules to nanoparticles (NPs) for developing precision therapeutics. In this regard, we address critical gaps in understanding the range/size of therapeutics, delivery window(s), and moreover, the potential impact of biological factors for optimal delivery parameters. Here we show, for the first time, to the best of our knowledge, that 24-h postfocal TBI female mice exhibit a heightened macromolecular tracer and NP accumulation compared with male mice, indicating sex-dependent differences in BBB permeability. Furthermore, we report for the first time the potential to deliver NP-based therapeutics within 3 days after focal injury in both female and male mice. The delineation of injury-induced BBB permeability with respect to sex and temporal profile is essential to more accurately tailor time-dependent precision and personalized nanotherapeutics. Impact statement In this study, we identified a sex-dependent temporal profile of blood/brain barrier disruption in a preclinical mouse model of traumatic brain injury (TBI) that contributes to starkly different macromolecule and nanoparticle delivery profiles post-TBI. The implications and potential impact of this work are profound and far reaching as it indicates that a demand of true personalized medicine for TBI is necessary to deliver the right therapeutic at the right time for the right patient.