Project Abstract The long-term goals of this project are to translate to the clinic innovative kidney-targeted therapeutics for glomerular disease. The interdisciplinary and translational team is led by a Biomedical Engineer with mentors and collaborators in Cell Biology, Nephrology, and a Pharmacology. End-stage kidney disease (ESKD) affects over 800,000 Americans, substantially increasing health and financial burdens related to dialysis or renal transplants. ESKD is preceded by chronic kidney disease (CKD), which arises from varying etiologies, including diabetes and hypertension, affecting 37 million Americans and over 800 million individuals worldwide. Taken together, proteinuric kidney diseases account for 90% of all ESKD at an estimated cost of $20 billion per year in the US. Substantial health disparities exist in the diagnosis and treatment of CKD, wherein African Americans are four times more likely than white Americans to progress to ESKD and represent 35% of all patients on dialysis. In addition to substantial socioeconomic risk factors, genetic and epigenetic alterations contribute to these disparities. Prior work by the collaborators at MSSM (Campbell, Wong) and others identified injury of the glomerular-resident podocytes as a partial driver of proteinuric CKD and progression to ESKD. Published studies by the lead PI (Williams) and mentor (Jaimes) discovered that safe, biocompatible polymeric mesoscale nanoparticles (MNPs) exhibit 26-fold selective targeting to the kidneys over any other organ. Those published studies used this MNP system to load various payloads, with 9 total published studies ranging from small molecules to biologics (peptides, siRNA, mRNA) and demonstrated their therapeutic efficacy in five separate rodent models of renal disease. We produced innovative data demonstrating an unexpected localization of these particles to the podocytes in the context of proteinuric glomerular disease, as opposed to prior studies showing targeting to the tubular epithelium within the kidneys. In this work, we will capitalize on this finding by delivering a therapeutic payload to the glomerulus in rodent models of glomerular disease. We will deliver the therapeutic amiloride, an FDA-approved diuretic used to treat hypertension. Studies have found that amiloride has off-target, podocyte protective effects, though clinical trials demonstrated limited efficacy in part due to poor pharmacology of the drug with respect to the kidney. Here, we propose to encapsulate amiloride within MNPs and to study the pharmacology and therapeutic efficacy of this formulation in several rodent models of glomerular disease. We plan complementary in vitro and in vivo studies to understand the mechanistic function of amiloride-loaded MNPs, as well as to investigate the unexpected finding of glomerular MNP targeting in the context of glomerular disease. We anticipate future work may pursue the encapsulation of more potent novel amiloride analogs, as well as ...