MOF-encapsulated nanozyme enhanced siRNA combo: Control neural stem cell differentiation and ameliorate cognitive impairments in Alzheimer's disease model

Neural stem cells (NSC) transplantation is garnering considerable attention in the treatment of neurodegenerative diseases that are associated with cognitive decline. Current methods are mainly based on neuron-directional differentiation and NSC niche components majorization to promote neurogenesis. Unfortunately, the pathologically high level of oxidative stress will damage the neurons derived from NSC during therapy, compromising the neurogenesis effect. Herein, a facile and effective strategy has been presented for modulation of neuron-directional differentiation and amelioration of oxidative stress by integrating antioxidative nanozymes (ceria) into metal-organic frameworks (MOF) for synergistically enhancing neurogenesis. Specially, small interfering RNA (siSOX9) and retinoic acid (RA) are loaded in the MOF. The H2O2-responsive MOF would release cargos in the lesion area to promote neuron-directional differentiation. Moreover, the integrated ceria can perform robust SOD and CAT mimetic activities, which are capable of eliminating ROS and circumventing its oxidative damage to newborn neurons, leading to the longer survival rate and more enhanced outgrowth of the newborn neurons. With the gratifying drug delivery efficiency of MOF and excellent antioxidative capacity of nanozymes, the rational-designed nanoparticles can considerably promote neurogenesis and improve the cognitive function of aged 3 x Tg-AD (triple transgenic AD mouse model) mice. Our work provides a new way to promote nerve regeneration with the help of nanozymes.