Arteriovenous fistula (AVF) maturation failure is a significant clinical problem in the hemodialysis patient population. Targeted nanomedicine is a rapidly growing area of research that is a promising approach to treat a wide spectrum of diseases, including cardiovascular disease and cancer. However, there is a paucity of research regarding the use of targeted nanomedicine to treat or prevent AVF maturation failure. Moreover, a better understanding of the pathways involved in AVF maturation failure is essential to develop novel therapeutic strategies, including targeted nanomedicine. The first objective of this proposal is to investigate the role of the transcription factor ETS proto-oncogene 1 (ETS-1), matrix metalloproteinase (MMP)-2, and MMP-9 in AVF development. Extensive work from our team has provided a strong rationale that the ETS-1 and MMP-2/9 axis is a major driver of pathological AVF remodeling. The second objective of this proposal is to investigate the effectiveness of drug-loaded P-selectin- targeted nanoparticles (NPs) to treat or prevent AVF maturation failure. AVF maturation failure is a regional problem, and therefore, targeted delivery of drugs to the AVF site may reduce dose-limiting toxicity, undesirable off-target effects, and unfavorable pharmacokinetics due to rapid drug degradation. We have recently engineered innovative NPs that display high affinity to P-selectin expressed in injured/activated endothelial cells. We found that AVF creation surgery was followed by increased P-selectin expression at the AVF site and that P-selectin- targeted NPs were preferentially aggregated at the AVF site. Furthermore, our team has developed various NPs for drugs with different sizes and chemical properties. The NPs for small drugs are based on fucoidan (a polysaccharide), which exhibits nanomolar affinity to P-selectin. The NPs for large drugs are based on liposomes conjugated with P-selectin ligands. Both carriers are made of natural and synthetic biocompatible materials that have been shown to be safe for use in humans. Our long-term goal is to develop novel therapeutic strategies to prevent AVF maturation failure that can ultimately be safely used in humans. Our central hypothesis is that maturation failure is caused by upregulated ETS-1 and MMP-2/9, and that the blockade of this pathway using nanoparticle-targeted delivery of drugs can improve AVF maturation. This hypothesis will be tested in two Specific Aims, using a combination of genetic approach (Aim 1) and nanotechnology (Aim 2). Aim 1: To determine the causal role of ETS-1 and MMP-2/9 in pathological AVF development in rodents with CKD. Aim 2: To investigate the therapeutic potency of ETS-1 and MMP-2/9 inhibition by targeted nanomedicine in enhancing AVF development in rodents with CKD. This translational project is innovative and significant, as it investigates a novel molecular pathway of AVF maturation failure and uses a novel nanotechnology for treating/preventing this...