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.

Septic shock is a life-threatening condition characterized by a dysregulated host immune response to microbial infection, resulting in excessive inflammation, oxidative stress, and progressive multi-organ failure. Innate immune pathways are hyperactivated, resulting in overproduction of reactive oxygen and nitrogen species (RONS), amplification of cytokine signaling, and widespread tissue injury. Despite early administration of antibiotics, fluids, and vasopressors, treatment outcomes remain suboptimal due to infection-overwhelming defenses, delayed pathogen identification, and the growing prevalence of multidrug-resistant microorganisms. Such limitations emphasize the need for antibiotic-independent therapeutic strategies which directly target immune dysregulation. The unique architecture and tunable physicochemical properties of hollow nanoparticles make them a promising class of immunomodulatory therapies for septic shock. Early-generation empty lipid nanoparticles caused excessive immune activation and cytotoxicity, but advances in nanomaterial engineering now allow precise control of size, surface charge, and composition, enabling anti-inflammatory and cytoprotective effects. Rationally designed hollow nanoparticles are now known to exhibit intrinsic antimicrobial activity, scavenge RONS, suppress oxidative stress responses, reprogram macrophage polarization toward anti-inflammatory phenotypes, and neutralize immunogenic bacterial toxins and antigens. Lipid-based and biomimetic hollow nanoparticles show promise as immunomodulatory therapies through distinct mechanisms of immune modulation. Currently, VBI-S, a phospholipid-based nanoparticle colloid, is undergoing Phase III clinical evaluation for the management of hypotension in patients with septic shock. More broadly, hollow nanoparticle platforms can represent adaptable, antibiotic-independent therapeutic strategies with the potential to improve outcomes in complex inflammatory conditions.

Septic shock is a life-threatening manifestation of sepsis characterized by dysregulated immune responses, excessive inflammation, oxidative stress, and progressive multi-organ dysfunction. Despite advances in antimicrobial therapy and supportive care, mortality remains high, highlighting the need for therapeutic strategies that target immune dysregulation in addition to infection control. The review evaluates the potential of hollow nanoparticles as immunomodulatory therapies for septic shock, focusing on lipid-based, polymeric, protein-based, biomimetic, inorganic, carbon-based, and hybrid nanoparticle platforms. Current evidence suggests that these systems can modulate key pathological processes through reactive oxygen and nitrogen species (RONS) scavenging, regulation of inflammatory signaling, macrophage modulation, neutralization of bacterial toxins and antigens, and, in some cases, direct antimicrobial activity. Among the available platforms, lipid-based and biomimetic nanoparticles appear to possess the greatest translational potential owing to their favorable immunomodulatory properties and improved biocompatibility. Nonetheless, several challenges continue to limit clinical translation, including nanoparticle-associated systemic and organ toxicity, unintended immunogenicity, limited long-term safety data, and the lack of standardized comparative studies across nanoparticle classes. Despite these limitations, the progression of VBI-S, a phospholipid nanoparticle formulation, to Phase III clinical evaluation highlights the growing clinical feasibility of such nanoparticle-based approaches for septic shock. Future research should focus on optimizing nanoparticle design, improving safety profiles, and establishing standardized preclinical and clinical evaluation frameworks. Collectively, the available evidence suggests that hollow nanoparticles represent a promising antibiotic-independent strategy for restoring immune homeostasis and improving outcomes in septic shock.