The synthetic DSPE-PEG₂₀₀₀-C3 peptide and DSPE-PEG₂₀₀₀-TPP were designed to modify the exosomes (EXO) by incubation, through which guide the C3/TPP-EXO to target the injured mitochondria of neurons. Then, C3/TPP-EXO was further used to encapsulate the curcumin (CUR) to enhance the solubility and bioavailability of the drug. By intravenously injected (i.v) into tau^p301s mutant transgenic (Tg) mice, C3/TPP-EXO facilitated the CUR to target the mitochondria of neurons and increase the entry efficiency of medication. To further reveal the mechanisms of drug entry, sodium azide (NaN₃), an energy inhibitor, was used to treat HT22 cells. The results demonstrated that the entrance efficiency of the engineered EXO is significantly affected suggesting that C3/TPP-EXO may target mitochondria through energy routes. To deeply study the exact molecular mechanisms of C3/TPP-EXO-CUR in treating AD, RNA-Seq was used to identify the relevant molecules. Through GO annotation, many genes are enriched in the pathways of mitochondria functions. Based on these RNA-Seq data, C3/TPP-EXO-CUR showed neuroprotective effects via modulating the protein expression of Bcl-2, Bax and caspase-3 in HT22 cells. To further confirm the in vitro results, the in vivo results revealed that C3/TPP-EXO-CUR treatment inhibited the phosphorylation of tau and protected neurons by inhibiting the apoptotic genes, leading to improve the memory decline of tau^p301s mice. Collectively, the current study revealed the benefits and mechanisms of C3/TPP-EXO-CUR for treating AD, which might provide a novel and effective therapeutic approach for the disease.