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

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.