Spatiotemporal “cut-and-repair” cascade: A cross-omics driven nanoemulsion breaks the gut–brain vicious cycle in Alzheimer's disease
Abstract
Alzheimer’s disease (AD) is increasingly viewed as a systemic condition driven by a self-reinforcing vicious cycle along the gut–brain axis, yet current therapies fail to simultaneously sever the peripheral source and repair central damage. Here, guided by our cross-omics discovery of a striking correlation ( r = 0.93) between gut microbiota dysbiosis and cerebral pathology in APP/PS1 transgenic mice, we engineered AxisGuard, a bioactive nanoemulsion featuring a “drug–excipient unification” strategy. By utilizing cinnamaldehyde as a functional oil phase to co-deliver curcumin, and incorporating functional polymers for dual-targeting, AxisGuard achieves a spatiotemporal cascade of intervention. It first “cuts the source” in the gut by remodeling the microbiome (reducing the Firmicutes/Bacteroidetes ratio by 73.8%) and suppressing peripheral inflammation. Sequentially, it “repairs the damage” in the brain by crossing the blood–brain barrier to clear A β deposits (61.2% reduction), reprogram microglia (28-fold M2/M1 reversal), and attenuate neuroinflammation. This study establishes a paradigm of quantitative, omics-driven nanomedicine that effectively breaks the gut–brain pathological loop, offering a potent systemic solution for AD.