Engineered Biomimetic Nanorobots Orchestrate Targeted Nose-to-Brain Delivery to Resolve Neuron-Glia Entanglement...

Intranasal administration enables direct brain drug delivery, showing promise for Parkinson's disease (PD) treatment. However, nose-to-brain delivery confronts sequential obstacles, including mucosal penetration, lesion-specific accumulation, and active targeting toward disease-relevant cells, demanding advanced nanotherapeutic design. Meanwhile, neural mitochondrial dysfunction and neuroinflammation constitutes two cross-interfering pathogeneses that drive PD progression. Herein, we developed an intelligent biomimetic nanoplatform (hPH‑RNPEC) based on Pueraria lobata-derived exosomes. The system is engineered with neutrophil-like membrane for inflammatory tropism, spatially staggered short unit of rabies virus glycoprotein (RVG) peptide for neuron-microglia dual targeting, and long motif of the tetrablock conjugation of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), pH-sensitive hydrazone bond, polyethylene glycol 2000 (PEG2k), and a histidine-switching peptide for efficient nasal mucosal penetration. Spatiotemporally, following intranasal administration in PD mice, hPH‑RNPEC can penetrate nasal mucosa, achieve inflammation‑directed lesion accumulation, and realize efficient cellular internalization. The system also co‑delivers endogenous exosomal miRNAs and therapeutic curcumin to mitigate neural mitochondrial damage and neuroinflammation collectively evidenced by mitochondrial function and inflammation assessment. Besides, single-cell RNA sequencing (scRNA-seq) further suggested the promotion of myelin repair and rewiring of neural circuits, which facilitate the remodeling of PD microenvironment. This study establishes an engineered biomimetic nanorobot platform for precise brain targeting and multifactorial intervention for PD treatment.