Biomimetic exosomal delivery of ginsenoside Rd reduces post-stroke depression via microglial reprogramming in a pathway involving EGFR/JAK2/STAT3

Post-stroke depression (PSD) represents a complex neuropsychiatric challenge characterized by persistent neuroinflammation and synaptic dysfunction, yet effective therapeutic interventions are constrained by the blood-brain barrier (BBB) and the lack of specific targets. Using a multidimensional screening strategy for Chaihu-Jia-Longgu-Muli Decoction (CLM), we identified ginsenoside Rd (Rd) as a key blood-absorbed bioactive constituent associated with Epidermal Growth Factor Receptor (EGFR) signaling. To overcome the bioavailability bottleneck, a biomimetic nanodelivery system is engineered by encapsulating Rd into microglia-derived exosomes (Exos@Rd). Based on the reported lesion-homing properties of microglia-derived exosomes, we developed a biomimetic Exos@Rd delivery system. Exosomal loading markedly enhanced the brain accumulation of Rd compared with free Rd. Mechanistically, it is demonstrated that aberrant EGFR activation functions as an upstream regulator of the JAK2/STAT3 cascade in microglia. Exos@Rd effectively suppressed this pathway and promoted anti-inflammatory microglial reprogramming, characterized by a shift from an M1-associated pro-inflammatory state toward an M2-associated anti-inflammatory profile. This microglia-centered anti-inflammatory regulation was accompanied by reduced oxidative stress and restoration of brain-derived neurotrophic factor (BDNF), postsynaptic density protein 95 (PSD95) and Synapsin I (SYN1) expression. In a PSD mouse model, Exos@Rd significantly restores cerebral perfusion and alleviates depressive-like behaviors. Collectively, this study elucidates a novel EGFR-driven neuroinflammatory mechanism and presents a bio-inspired strategy for precision CNS drug delivery, offering a promising therapeutic paradigm for PSD.