Engineered exosomes improve the effects of curcumin on protecting mitochondria of neurons in Alzheimer's disease.

The synthetic DSPE-PEG-C3 peptide and DSPE-PEG-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 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 (NaN), 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 results, the 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 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.