Traceable Co-delivery System Controlling Neural Stem Cells Differentiation For Alzheimer's Disease Therapy

Alzheimer's disease(AD) is the most prevalent age-related neurodegenerative disorder. The predominant pathologies of AD are gliosis and widespread neuronal loss, which progressively cause impairments in the memory and cognitive functions.Current therapies, such as treatment with acetylcholinesterase inhibitors to enhance the cholinergic function, are inefficient due to the great hindrance at the blood–brain barrier(BBB) and their poor target ability to the diseased sites. Therefore, it is necessary to develop more efficient methods to overcome these drawbacks.Neural stem cells(NSCs) are becoming an increasingly attractive option because of their non-immunogenicity and ability to differentiate into neurons. Generally, NSCs are stereotactically transplanted into the hippocampus of patients, which could avoid the interference of the BBB. Furthermore, NSCs have the capacity of targeting migration to the diseased sites after transplantation. Therefore, these neurons could remedy the neuronal loss at the diseased site. However, there are two disadvantages limiting their application. Firstly, the differentiation of NSCs to neurons is far from successful because of their multi-directional differentiation. It has been reported that only a small proportion of NSCs adopted a neuronal state after transplantation, while the majority differentiated into astrocytes. Secondly, it is hard to track NSCs in real time after transplantation into the brain of patients, which is problematic as the therapeutic efficiency of NSCs depends on their transplantation site and their migration. Therefore, the successful application of NSCs would be based on controlled differentiation of NSCs to neurons and long-term monitoring in real time.Although neural stem cells(NSCs) could differentiate into neurons to remedy Alzheimer's disease(AD), the uncontrolled differentiation and difficult tracking in real time seriously impede their application. To solve those problems, we used retinoic acid(RA) and small interfering RNA targeting SOX9 protein to control NSC differentiation into neurons. Superparamagnetic iron oxide nanoparticles(SPIONs) with high relaxivity were used to monitor NSCs in real time. To overcome their intrinsic deficiencies and enhance their combined effect, we developed traceable poly(carboxybetaine)(PCB) based PHEMA50-RA-PCB20-CPP/SPIONs/si SOX9 NPs(AB20C/SPIONs/siRNA NPs) for AD therapy. The NPs could efficiently control the differentiation of NSCs into neurons, which significantly attenuated neurons loss and rescued the memory deficints in 2x Tg-AD mice. Meanwhile, the system could monitor the transplantation site and migration of NSCs in real time. Therefore, we believe that the traceable PCBylated NPs will open up a new avenue for AD treatment.