A Nanoformulation‐Mediated Multifunctional Stem Cell Therapy with Improved Beta‐Amyloid Clearance and Neural Regeneration for Alzheimer's Disease

Abstract Alzheimer's disease (AD) is a common dementia that is currently incurable. The existing treatments can only moderately relieve the symptoms of AD to slow down its progress. How to achieve effective neural regeneration to ameliorate cognitive impairments is a major challenge for current AD treatment. Here, the therapeutic potential of a nanoformulation‐mediated neural stem cell (NSC) therapy capable of simultaneous Aβ clearance and neural regeneration is investigated in a murine model. Genetically engineered NSCs capable of stably and continuously expressing neprilysin (NEP) are developed to enhance Aβ degradation and NSC survival in the brain. A PBAE‐PLGA‐Ag 2 S‐RA‐siSOX9 (PPAR‐siSOX9) nanoformulation with high gene/drug deliverability is synthesized to overcome AD microenvironment‐associated adverse effects and to promote neuronal differentiation of the NEP‐expressing NSCs. For achieving accurate stereotactic transplantation, Ag 2 S quantum‐dot‐based fluorescence imaging is used to guide NSC transplantation in real time. This strategy shows numerous benefits, including efficient and long‐lasting Aβ degradation, improved neural regeneration, and accurate cell transplantation. It is shown that a single administration of this therapy achieves long‐term efficacy (6 months) with respect to memory reversal and improvement of learning deficits.