Engineered hUC-MSC exosomes loaded with pterostilbene induce Nrf2/SKN-1-dependent microglial M2 polarization and neuroprotection in Alzheimer's disease in vitro and in Caenorhabditis elegans.

Alzheimer's disease (AD) is aggravated by overactivated pro-inflammatory M1 microglia. Although pterostilbene (PTE) possesses anti-oxidative and anti-neuroinflammatory activity, its therapeutic application in AD is limited by poor aqueous solubility and weak blood-brain barrier (BBB) penetration. Here, we fabricated pterostilbene-loaded human umbilical cord mesenchymal stem cell exosomes (PTE-Exos) with enhanced BBB permeability via freeze-thaw loading. In vitro BBB and microglia-neuron co-culture models were used to evaluate targeting, immunomodulation, and neuroprotection, while Nrf2 loss-of-function assays and transgenic Caenorhabditis elegans AD strains enabled cross-species mechanistic verification. PTE-Exos efficiently cross the BBB in vitro and selectively accumulate in activated microglia, shifting CD86⁺ M1 cells toward the CD206⁺ anti-inflammatory M2 phenotype, reducing pro-inflammatory cytokines, restoring Aβ phagocytosis and alleviating Aβ-induced tau hyperphosphorylation and synaptic injury. Mechanistically, PTE-Exos simultaneously suppressed the NLRP3 inflammasome and NF-κB signaling and activated the Nrf2/HO-1 cascade to mitigate mitochondrial oxidative stress, and stabilized Nrf2 by attenuating its K48-linked polyubiquitination and prolonging its apparent half-life in a proteasome-dependent manner while preserving the KEAP1-Nrf2 complex. Nrf2 knockdown or pharmacological inhibition abolished these protective effects, and SKN-1 silencing eliminated PTE-Exos-mediated neuroprotection in C. elegans. Collectively, hUC-MSC exosomes resolve the pharmacokinetic limitation of PTE and remodel microglial phenotypes via the conserved Nrf2/SKN-1 axis, providing a biomaterial foundation for Nrf2-targeted nanotherapies against neuroinflammatory neurodegeneration.