Alzheimer’s disease (AD) is the most common neurodegenerative disease, which is associated with extracellular deposition of amyloid-β proteins (Aβ). It has been reported that triptolide (TP), an immunosuppressive and anti-inflammatory agent extracted from a Chinese herb Tripterygium wilfordii, shows potential neuroprotective effects pertinent to AD. However, the clinical use of TP for AD could be hampered due to its high toxicity, instability, poor water solubility, and nonspecific biodistribution after administration. In this paper, we reported a kind of multiple-coated PLGA nanoparticle with the entrapment of TP and surface coated by chitosan hydrochloride, Tween-80, PEG20000, and borneol/mentholum eutectic mixture (MC-PLGA-TP-NP) as a novel nasal brain targeting preparation for the first time. The obtained MC-PLGA-TP-NP was
147.5
±
20.7
nm with PDI of
0.263
±
0.075
, zeta potential of
14.62
±
2.47
mV, and the entrapment efficiency and loading efficiency of
93.14
%
±
4.75
%
and
1.17
±
0.08
%
, respectively. In comparison of TP, MC-PLGA-TP-NP showed sustained-release profile and better transcellular permeability to Caco-2 cells in vitro. In addition, our data showed that MC-PLGA-TP-NP remarkably reduced the cytotoxicity, attenuated the oxidative stress, and inhibited the increase of the intracellular Ca2+ influx in differentiated PC12 cells induced by Aβ1-42. Therefore, it can be concluded that MC-PLGA-TP-NP is a promising preparation of TP, which exerts a better neuroprotective activity in the AD cellular model.