Microglia-targeted Panax notoginseng polysaccharide nanoparticles alleviate Alzheimer's disease via AMPK-mTOR/HIF-1α-mediated immunometabolic reprogramming.

Alzheimer's disease (AD) is increasingly recognized as an immunometabolic disorder characterized by a self-reinforcing cycle of neuroinflammation and glycolytic reprogramming in microglia. Herein, we developed KPBIT@NPs, a microglia-targeted polysaccharide-based nanomedicine. Unlike many conventional nanocarriers that mainly serve as passive delivery vehicles, KPBIT@NPs employ the natural macromolecule Panax notoginseng polysaccharide (PNP) to construct a dual-functional, responsive nanoparticle platform. Through rational engineering via phenylboronic ester grafting, the polysaccharide backbone enables amphiphilic self-assembly and efficient co-loading of icaritin and tanshinone IIA, while allowing pathological reactive oxygen species (ROS)-triggered disassembly. In addition, surface decoration with the KLVFFAED peptide facilitates blood-brain barrier transport and targeted accumulation in activated microglia. Mechanistically, KPBIT@NPs activate AMP-activated protein kinase and suppress the mechanistic target of rapamycin/hypoxia-inducible factor 1α signaling axis, thereby reversing pathological glycolytic skewing and restoring mitochondrial oxidative metabolism. This coordinated regulation disrupts the inflammation-metabolism feed-forward loop and successfully reprograms microglia from a pro-inflammatory, metabolically stressed state toward a reparative phenotype. In AD animal models, KPBIT@NPs effectively restore cerebral energy metabolism, markedly reduce amyloid-β deposition, alleviate neuroinflammation, preserve neuronal integrity, and ultimately rescue cognitive deficits. This study establishes an innovative nanotherapeutic paradigm based on bioactive polysaccharides and offers a promising materials strategy for neurodegenerative diseases driven by coupled metabolic and inflammatory dysregulation.