Calcium Folate Nanoparticles as Dual‐Functional Neural Inducing Factors to Promote the Differentiation of Neural Stem Cells into Cholinergic Neurons

Abstract Alzheimer's disease (AD) features the loss of cholinergic neurons in the mesopontine area. There is no available approach to repair the damaged cholinergic neurons. Neural stem cell (NSC)‐based therapy is a promising strategy for the treatment of AD. However, it is a challenge to direct the NSCs to specifically differentiate into cholinergic neurons. Herein, calcium folate (CaFO) nanoparticles are synthesized through a facile nanoprecipitation approach for promoting the differentiation of NSCs into functional cholinergic neurons. After uptake by NSCs, the CaFO nanoparticles are distributed in the lysosomes (pH< 5.5) and can be decomposed into Ca 2+ and folic acid in the acidic environment. The Ca 2+ can accelerate the differentiation rate of NSCs while the folic acid can direct the NSCs to differentiate into cholinergic neurons. The in vitro experiments demonstrate that under the stimulation of CaFO nanoparticles, the NSCs differentiate into functional cholinergic neurons within 5 d. Animal experiments prove that the CaFO nanoparticles also promote the neuronal differentiation of NSCs in vivo, leading to the improvement in the cognitive memory ability of AD mice. This study provides a new strategy to induce the quick differentiation of NSCs into functional cholinergic neurons, which is promising for the treatment of AD.