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Microglia as an important type of innate immune cell in the brain have been considered as an effective therapeutic target for the treatment of central nervous degenerative diseases. Herein, we report cell membrane coated novel biomimetic Cu 2- x Se-PVP-Qe nanoparticles (denoted as CSPQ@CM nanoparticles, where PVP is poly(vinylpyrrolidone), Qe is quercetin, and CM is the cell membrane of neuron cells) for effectively targeting and modulating microglia to treat Parkinson's disease (PD). The CSPQ nanoparticles exhibit multienzyme activities and could effectively scavenge the reactive oxygen species and promote the polarization of microglia into the anti-inflammatory M2-like phenotype to relieve neuroinflammation. We reveal that biomimetic CSPQ@CM nanoparticles targeted microglia through the specific interactions between the membrane surface vascular cells adhering to molecule-1 and α4β1 integrin expressed by microglia. They could significantly improve the symptoms of PD mice to result in an excellent therapeutic efficacy, as evidenced by the recovery of their dopamine level in cerebrospinal fluid, tyrosine hydroxylase, and ionized calcium binding adapter protein 1 to normal levels. Our work demonstrates the great potential of these robust biomimetic nanoparticles in the targeted treatment of PD and other central nervous degenerative diseases.

Mitochondrial dysfunction of neurons is the core pathogenesis of incurable Parkinson's disease (PD). It is crucial to ameliorate the mitochondrial dysfunction of neurons for boosting the therapy of PD. Herein, the remarkable promotion of mitochondrial biogenesis to ameliorate mitochondrial dysfunction of neurons and improve the treatment of PD by using mitochondria‐targeted biomimetic nanoparticles, which are Cu2‐xSe‐based nanoparticles functionalized with curcumin and wrapped with DSPE‐PEG2000‐TPP‐modified macrophage membrane (denoted as CSCCT NPs), is reported. These nanoparticles can efficiently target mitochondria of damaged neurons in an inflammatory environment, and mediate the signaling pathway of NAD+/SIRT1/PGC‐1α/PPARγ/NRF1/TFAM to alleviate 1‐methyl‐4‐phenylpyridinium (MPP+)‐induced neuronal toxicity. They can reduce the mitochondrial reactive oxygen species, restore mitochondrial membrane potential (MMP), protect the integrity of mitochondrial respiratory chain, and ameliorate mitochondrial dysfunction via promoting mitochondrial biogenesis, which synergistically improve the motor disorders and anxiety behavior of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐induced PD mice. This study demonstrates that targeting mitochondrial biogenesis to ameliorate mitochondrial dysfunction has a great potential in the treatment of PD and mitochondria‐related diseases. [ABSTRACT FROM AUTHOR]