Title : Magnetic edematous brain-derived cell membrane nanovesicles reveal targets and treatments for traumatic brain injury
Abstract:
Traumatic brain injuries (TBIs) impact the breadth of society but remain without any approved pharmacological treatments. Mass effect, where a focal lesion or contusion causes the surrounding brain tissue to be compressed due largely to edema, exacerbates neurodegeneration and can contribute to poor outcomes. In this work, we develop magnetic edematous brain-derived cell membrane nanovesicles (Mag-CMVs) to screen FDA-approved drugs for effective edema relief in a controlled cortical impact (CCI) mouse model and demonstrate in vivo validation.
After optimizing injury parameters for maximal edema, 16-week-old male C57BL/6 mice received CCI focal TBIs (5 mm impactor; 3 m/s; 300 ms dwell; 0.996 mm depth) and were transcardially perfused 24 hours post-injury. Cells from the edematous ipsilateral region were isolated via papain dissociation, centrifuged, snap-frozen, mechanically disrupted, and combined with phase-change materials, ions, ATP, a deuterated tracer, and magnetic nanodots to form Mag-CMVs. These Mag-CMVs were screened against a 640-compound FDA-approved drug panel, with top hits tested in vivo at 1 and 12 hours p.i., and then sacrificed at 24 hours p.i.. The leading candidates, FM_04 and FM_02 (p < 0.05), were further examined for dose-response relationships. The top candidate is now undergoing spatial transcriptomic analysis for comparative profiling with a sham TBI cohort from our previous study.
In the first 24 hours after injury, the acute phase, cerebral edema contributes to deleterious neurodegeneration. The time frame employed in this investigation reveals already FDA-approved therapeutics with striking, quantifiable acute edema-relieving capabilities. To expand this work, our spatial transcriptomic analysis will uncover which cellular and molecular pathways can be targeted in the first 24 hours p.i. to develop targeted acute TBI therapies in the future.
