A lymphotropic biomimetic nanoplatform reverses sleep deprivation-induced cognitive deficits by reprogramming microglial phenotypes

Sleep deprivation (SD) drives persistent neuroinflammation and cognitive impairment, yet the underlying cellular and molecular mechanisms remain incompletely understood. Using single-cell transcriptomics of SD mouse brains, we identify an irreversible microglial phenotype shift characterized by downregulation of the homeostatic marker Tmem119 and upregulation of the disease-associated gene APOE . To therapeutically reverse this pathology, we engineered a biomimetic nanoplatform (ATABP) that co-delivers Tmem119-encoding plasmid DNA and an APOE inhibitor. The platform is cloaked with activated microglial membrane for inflammation-directed homologous targeting, and functionalized with ApoA1-mimetic peptides to enable lymphatic trafficking for brain delivery. In SD mice, ATABP treatment restored the homeostatic microglial phenotype, attenuated neuroinflammation, reduced amyloid-β pathology, and rescued cognitive performance without systemic toxicity. This study establishes Tmem119/APOE imbalance as a critical driver of SD-induced neuropathology and demonstrates that lymph-targeted biomimetic nanodelivery offers a promising strategy for microglial reprogramming in SD and potentially other neurological conditions.