Sepsis-associated encephalopathy (SAE) is a severe neurological complication of sepsis, for which current therapeutic options remain limited. There is an urgent need for innovative strategies that simultaneously target both central and peripheral pathophysiological mechanisms. In this study, we developed a microalgae-nanoparticle multistage biosystem, CV@MT-NPs, by electrostatically assembling melatonin-loaded, quaternary chitosan-modified liposomes (MT-NPs) onto(CV) microalgae. The resulting CV@MT-NPs enabled sustained melatonin release and significantly prolonged systemic circulation and brain retention of melatonin. In an LPS-induced murine SAE model, CV@MT-NPs markedly improved survival, attenuated cognitive deficits and anxiety-like behaviors, reduced clinical severity, and mitigated body weight loss. Mechanistically, MT-NPs released from CV@MT-NPs entered the brain, where they preserved blood-brain barrier integrity by restoring tight junction proteins and re-establishing astrocyte-endothelial coupling. Furthermore, they suppressed neuroinflammation by inhibiting microglial hyperactivation, promoting microglial homeostasis, attenuating astrogliosis, and protecting mitochondrial structure and function. Beyond the central nervous system, MT-NPs also ameliorated systemic inflammation, restored intestinal barrier integrity, and enhanced M2 macrophage polarization through inhibition of the NF-κB signaling pathway. Notably, the CV component played a complementary role by rebalancing the gut microbiota, specifically enriching beneficial short-chain fatty acid-producing bacteria, and elevating levels of acetic, propionic, and butyric acids in both the gut and the brain. Critically, comprehensive biocompatibility assessments revealed no evidence of acute or chronic toxicity. Collectively, CV@MT-NPs represent a multifunctional, gut-brain axis-modulating therapeutic platform that, when administered prophylactically, demonstrates significant potential to concurrently ameliorate central neuropathology and peripheral immune-metabolic dysfunction, offering a promising preventive strategy for SAE. Chlorella vulgaris
