Immunomodulatory Empty/Hollow Nanoparticles as Potential Therapeutic Strategies for Septic Shock

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.