A tunable brain-targeted PEGylated ginsenoside Rg1 derivative disrupts the ROS-mediated inflammasome-pyroptosis cascade to ameliorate Alzheimer's cognitive deficits.

The pathogenic cascade of oxidative stress, neuroinflammation, and pyroptosis serves as a core driving factor in the pathogenesis and progression of Alzheimer's disease (AD). Although ginsenoside Rg1 exhibits pleiotropic neuroprotective activities, its poor blood-brain barrier (BBB) permeability severely hinders its clinical translation. To overcome this limitation, a brain-targeted delivery system was constructed using a covalent conjugation strategy, linking purified Rg1 with rhodamine B-modified polyethylene glycol (PEG) of varying chain lengths (Rg1s-PEG). After screening, the derivative Rg1s-PEG-600 was identified as achieving an optimal balance between hydrophilic stealth properties and steric hindrance, demonstrating enhanced brain accumulation and favorable biosafety profiles. In both in vitro and in vivo models of lipopolysaccharide-induced acute neuroinflammation, Rg1s-PEG-600 attenuated reactive oxygen species (ROS) accumulation, inhibited canonical neuronal pyroptosis mediated by the NLRP1/3 inflammasomes, and significantly ameliorated behavioral deficits and synaptic loss. Furthermore, in chronic 5xFAD transgenic mice, systemic administration of Rg1s-PEG-600 for 12 weeks markedly reversed spatial memory decline, anxiety-like behavior, and synaptic protein depletion. Mechanistic studies further revealed that this targeted nanotherapeutic not only suppressed the ROS-NLRP1 signaling axis and subsequent neuronal pyroptosis in the AD brain but also comprehensively inhibited amyloidogenesis and Tau hyperphosphorylation. This work provides a promising, multitarget nanotherapeutic strategy to overcome BBB limitations and disrupt the complex pathological networks underlying neurodegenerative diseases.