## 3 Application of Nanotechnology in Stem-Cell Therapy
### Nanodeliery of Stem-Cell for Neuron Recovery  
Neurogenesis occurs via neural stem cells which are located in special points called niches, such as subventricular zone, subgranular zone in the brain and central canal (CC) in the spinal cord [60; 61]. NSC-based therapeutic approach have the potential of neuron repair or replacement by NSC transplantation at the injured point. However, the most important limitation in this method is the high rate of implanted cell mortality, availability and metastases. Thus, inducing endogenous NSC in situ to stimulate their differentiation to neural cells is a probable solution for this problem [62; 63]. While this method may address the issues related to NSC transplantation, selective NSC targeting is the more difficult restriction for development of transplantation approach. [PERSON] et al. have provided lipid nanocapsules (LNC) to encapsulate the NFL, a synthetic peptide involved in differentiation of SVZ-NSC. The most significant advantage of NFL compared to other cell penetrating peptides is the stronger interaction of NFL with LNC via energy-independent mechanism. They demonstrated that NFL-LNC complexes have preferably been taken up by neural brain stem cell, while they did not interact with spinal cord stem cells. In vivo results confirmed in vitro findings, indicating NFL-LNC has a good potential for delivering bioactive molecules to brain targeting neural stem cells [64]. Metal oxide NPs such as iron oxide (Fe\({}_{3}\)O\({}_{4}\)), cerium oxide (CeO), and zinc oxide (ZnO) nanoparticles have all been developed to be used in imaging techniques and also as therapies to minimize oxidative stress in the brain [65]. Applying an external magnetic field prior to systemic injection of Fe\({}_{3}\)O\({}_{4}\) NPs can improve passing the NPs through the blood brain barrier (BBB) and reaching the brain parenchyma.  
The heterogeneity and uniformity of stem-cell differentiation is a critical issue to avoid tumorigenesis. The activation of immune response due to inhospitable host environment is another obstacle for successful transplantation of stem cells for regenerative purposes. Development of intracellular delivery of functional molecules, such as drugs, DNA, RNAi, peptides and proteins is a practical solution to control the stem-cell differentiation [66; 67]. The dynamic external magnetic of SPIO gold NPs coated with nerve growth factor (NGF) enable them to induce neuron growth and differentiation. Moreover, immobilization of short hairpin RNA (shRNA) onto the Fe\({}_{3}\)O\({}_{4}\) NPs can reduce neural apoptosis in a model of Parkinson's disease [65]. Among several biomolecules capable to differentiate stem-cell progeny to desired lineage-specific precursors [68], retinoic acid (RA) is an ideal candidate to activate gene transcription related to cell proliferation, differentiation and apoptosis. Manipulation of endogenous stem cells from their neurogenic niche, can trigger neurogenesis and enhances regenerative potential of brain. In a study by [PERSON] et al. the ability of polyelectrolyte NPs to intracellularly release of RA and consequently to induce differentiate the SVZ cells into neurons was investigated. They demonstrated that these NPs in concentrations below 100-ug/mL have no harmful cytotoxic effects and do not interfere with cell morphology and proliferation. They showed RA-NP internalization improved neurogenesis and also revealed the importance of their influence in stem-cell differentiation; and thus, they can be considered as an excellent choice for drug delivery into the brain and cells. These modified NPs offers an opportunity for delivery of neurogenic-inducing factors such as key proteins, peptides, DNA and RNAi which ultimately can aid in neurodegenerative disease treatment [69]. Thus, the nanoparticles with covalently conjugated drugs can transport bioactive compounds and functional factors due to their surface characteristics, size and charge (Figure 5).