Phospholipid Nanoparticle Resuscitation Preserves Neuronal Integrity and Cognitive Recovery Without Exacerbating Neuroinflammation Following Hemorrhagic Shock-Induced Clinical Death

Background/Objectives: Severe hemorrhagic shock progressing to clinical death remains a major cause of mortality and long-term neurological morbidity despite advances in trauma care. While current resuscitation strategies restore circulation, their ability to preserve brain structure and function following global ischemia–reperfusion injury remains limited. Hemorrhagic shock induces widespread neuronal vulnerability, particularly within the hippocampus and prefrontal cortex, contributing to persistent cognitive and behavioral deficits among survivors. Methods: Using a rat model of hemorrhagic shock-induced clinical death, we evaluated whether resuscitation with VBI-1, a phospholipid nanoparticle-based colloid, supports neurological recovery compared with whole blood-based resuscitation. Animals underwent controlled exsanguination to the point of clinical death, followed by rapid intra-arterial reanimation with either shed whole blood or VBI-1. Two phases of study were performed: histological evaluation of tissues 12 h after resuscitation and, in a separate cohort of animals, longitudinal behavioral recovery over 30 days. Histology focused on evaluating neuronal integrity in the hippocampal CA1 region and prefrontal cortex, neuronal functional status, and microglial responses. Sex was analyzed as a biological variable. Results: Resuscitation with VBI-1 is associated with sustained behavioral recovery, with pronounced sex-dependent effects favoring females during the subacute-to-chronic recovery phase. VBI-1 preserved neuronal density, laminar organization, and neuronal functional integrity in ischemia-vulnerable brain regions. This, and neuronal preservation, correlated with hippocampal-dependent working memory performance. Importantly, resuscitation with VBI-1 did not increase microglial density, coverage, or spatial organization, exacerbating the neuroinflammatory burden. Conclusions: These findings demonstrate that phospholipid nanoparticle-based resuscitation confers meaningful neurological recovery following profound circulatory collapse, highlighting the importance of evaluating resuscitation agents based on long-term brain outcomes.