However, this technique also induced a pro-inflammatory response by activating microglia, indicating a potential damaging effect that needs to be carefully considered when applying QDs to stem cell therapy [64]. 2.3. increases and the global population ages. In the United States, Alzheimer’s alone is the 6th leading cause of death, with an annual economic cost over $236 billion [1]. Treatment MI-773 (SAR405838) of neurodegenerative disease has been slow to progress due to contradicting hypotheses of the physiological causes of disease, alongside extreme difficulty in shuttling drugs across the blood-brain barrier (BBB) [2,3]. Additionally, widespread neuronal cell death is particularly difficult to target, and lack of robust regenerative capacity in the central nervous system (CNS) renders most treatments ineffective [4,5]. Two major avenues of research to address these problems are stem cell transplantation, often directly into the brain, and nanoparticles that can cross the BBB [2,5,6]. The joining of these two fields is especially useful for the combination of diagnostics and treatment, commonly termed theranostics [7]. Here we review the current status of using nanomedicine in concert with stem cell therapy to diagnose, track progression, and treat neurodegenerative diseases. 1.1. Biology of the BBB The brain MI-773 (SAR405838) is incredibly sensitive to toxins in the bloodstream, and requires a specialized microenvironment for WNT5B optimal function [8]. The BBB creates a selective barrier composed of cerebral capillary endothelial cells linked by tight junctions that prevent movement of molecules between cells. Additionally, the P-glycoprotein (P-gp) pump on endothelial cells actively effluxes cytotoxic molecules unidirectionally across the apical membrane and into the luminal space, thereby removing foreign molecules that bypass the BBB [2,9]. The barrier is further reinforced by microglia, pericytes, and astrocytes that sheath the endothelial tube [10,11]. Small, lipophilic molecules and gases can diffuse across the BBB down a concentration gradient, while large and hydrophilic molecules require the use of transporters. Three mechanisms of transport exist in the BBB: carrier-mediated transport (CMT), receptor-mediated transcytosis (RMT), and adsorptive-mediated transcytosis (AMT) (Fig. 1).CMT principally transports relatively small molecules and nutrients like glucose, amino acids, and ascorbic acid using protein carriers. RMT and AMT, on the other hand, use vesicles to endocytose and shuttle larger proteins and molecules across the BBB. While RMT is highly selective due to the requirement of receptor-ligand recognition, AMT depends on less specific interactions between cationic compounds and the negatively charged sulfated proteoglycans on the endothelial plasma membrane [12,13]. Nanoparticle delivery has taken advantage of both the specificity of RMT and the pliability of AMT, which allow for preferential drug targeting to the brain and independence from membrane receptors, respectively [11]. Delivery of nanomedicine that can cross the BBB is considered noninvasive, and is one of the most promising strategies of treating neurodegenerative disease. Open in a separate window Fig. 1. The biology of the blood-brain barrier is crucial for understanding how drugs can reach the brain. Three major transport mechanisms exist: carrier-mediated MI-773 (SAR405838) transport (left), receptor-mediated transcytosis (center), and adsorptive-mediated transcytosis (right). Paracellular diffusion can also occur between epithelial cells. 1.2. Drug clearance Many drugs, including nanomedicine, are quickly degraded when exposed to the circulatory system. The reticuloendothelial system (RES), also known as the mononuclear phagocyte system MI-773 (SAR405838) (MPS), consists of immune cells that recognize and clear drugs within a few hours of administration. Macrophages are the MI-773 (SAR405838) primary actors of the MPS, and clear nanoparticles in the liver or spleen as blood flows through these organs [14,15]. Encapsulation in nanoparticles is not sufficient for drugs to evade clearance, but a number of surface modifications on top of nanoparticles are highly effective in increasing stability and circulation time. These surface modifications can be applied to almost every type of nanotechnology described below. The most successful modification is polyethylene glycol (PEG), which improves both the stability and biological performance of many nanoparticles.