Background/Objectives: Exsanguination is a leading cause of preventable death in military and civilian settings due to extensive blood loss and hemorrhagic shock, which trigger systemic effects such as impaired tissue perfusion, hypoxia, inflammation, and multi-organ dysfunction. Standard resuscitation restores blood volume but fails to address critical aspects of hemorrhagic shock, including inflammation, coagulopathy, and reperfusion injury. To address these limitations, novel phospholipid nanoparticle (PNP)-based resuscitative fluids, VBI-S and VBI-1, were developed to modulate nitric oxide (NO) levels, improving hemodynamic stability, tissue oxygenation, and reducing inflammatory injury. This study assessed the potential of novel phospholipid nanoparticle fluids, VBI-S and VBI-1, as resuscitative agents for severe hemorrhagic shock by evaluating their ability to regulate nitric oxide, restore blood pressure, and mitigate ischemia–reperfusion injury. Methods: This study involved two phases with Sprague Dawley rats (n = 6 per group). Phase one, lasting 4 h, included four groups: blood, Ringer’s lactate, VBI-S, and VBI-1. Phase two, lasting 12 h, comprised sham, blood, and VBI-1 groups. Under anesthesia, one femoral artery was catheterized for blood pressure monitoring, and blood withdrawal from the other induced apnea. Reanimation was performed using an intra-arterial infusion of shed blood, Ringer’s lactate, VBI-S, or VBI-1. Tissue samples were analyzed histologically and for oxidative DNA damage via immunofluorescence. Chemiluminescence and rheology assessed nitric oxide interactions and viscosity. Data were analyzed using ANOVA. Results: VBI-1 and shed blood increased mean arterial pressure (MAP) from <10 mmHg to survivable levels sustained for 12 h, with VBI-1 showing significantly higher MAP at 3–4 h. Rats treated with Ringer’s lactate died within 30 min. Histology revealed reduced organ damage in VBI-1-treated rats compared to shed blood. Immunohistochemistry indicated significantly less oxidative DNA damage (p < 0.001) in VBI-1-treated rats. VBI-1 exhibited superior viscosity and nitric oxide binding. Conclusions: VBI-1 demonstrates strong potential as a resuscitative fluid, offering blood pressure restoration, reduced oxidative damage, and enhanced tissue perfusion, with significant implications for use in resource-limited and pre-hospital settings.

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.