A 3-N nose-to-brain urolithin a nanomotor targeting microglial mitophagy in neuroinflammation

Cognitive impairment is the primary manifestation of neuroinflammation-related central nervous system diseases. Intranasal administration is an effective method, bypassing the blood-brain barrier and delivering drugs to the brain. Herein, we designed a biomimetic self-propelled nanomotor with an inflammation-targeting capacity. This nanomotor comprised a hollow mesoporous manganese dioxide (HMnO₂) core and a polydopamine (PDA) shell. HMnO₂ effectively catalyzed the conversion of endogenous H₂O₂ into H₂O and O₂, enabling the movement of the nanomotor into a wider area to reduce neuroinflammation. The nanomotor was loaded with the natural compound urolithin A (UA), which significantly improved the bioavailability of the compound and enhanced mitophagy. Furthermore, PDA modification imparted the nanomotor with strong adhesive properties, enabling them to anchor effectively to the olfactory nerve and enhancing delivery to the brain. In vitro, PDA@HMnO₂@UA alleviated mitochondrial dysfunction, oxidative stress, and inflammation levels by enhancing mitophagy in lipopolysaccharide (LPS)-induced BV2 cells. Following intranasal administration, PDA@HMnO₂@UA exerted neuroprotective effects by alleviating microglial activation, neuroinflammation, and neuronal loss, ultimately rescuing the neurocognitive function in the LPS-induced neuroinflammation model. In summary, this study presents an ideal nanomotor platform based on the 3-N strategy, which means "Nanomotor loaded with a Natural product to traverse a Natural anatomical pathway," that can alleviate cognitive impairments caused by neuroinflammation, offering a promising delivery approach for treating neuroinflammatory diseases.