Pathology-informed nanodelivery for sepsis therapy: design principles and translational challenges

Sepsis is difficult to treat because infection-triggered host responses rarely remain confined to one pathway. Immune dysfunction, endothelial injury, microcirculatory disturbance, programmed cell death, and multiple organ dysfunction syndrome (MODS) often overlap during disease progression. This overlap makes it necessary to evaluate nanodelivery systems according to the pathological barrier and treatment window they are designed to address, rather than by material composition alone. Here, we review recent sepsis-oriented nanodelivery studies through four intervention routes: pathogen clearance, toxin neutralization, immune modulation, and multimodal synergistic therapy. We discuss how targeting design, biomimetic interfaces, microenvironment-responsive release, and multifunctional integration have been used to improve local antibacterial activity, remove toxic mediators, regulate dysregulated immune responses, and reduce secondary organ injury. We also examine why many promising platforms remain difficult to translate, with particular attention to patient heterogeneity, disease-stage selection, altered biodistribution in septic hosts, biosafety, manufacturing reproducibility, and clinical-trial design. By linking pathological barriers with delivery-system design and clinical positioning, this review provides a pathology-informed framework for developing nanodelivery systems as adjunctive strategies for precision sepsis therapy.