CORE B - ABSTRACT Despite advancements in the development of immunosuppressive agents, the management of lupus nephritis (LN) remains challenging. Although newer classes of immune therapeutics (ITs) have been developed, their overall efficacy remains virtually unchanged. More intense IT regimens create serious complications, including infection, malignancy, metabolic disorders, and microvascular toxicity. In general, these toxicities contribute to accelerated cardiovascular disease, the leading cause of death in patients with LN. Therefore, the development of more effective targeted ITs is a major unmet medical need. The field of nanotechnology has generated significant interest in medicine with inherent capacity to increase therapeutic efficacy due to delivery of a higher dose of these payloads to the site of tissue injury (e.g., kidney in LN), minimizing their systemic toxicity by limiting the dose needed to obtain the optimal clinical effect. As the vast majority of nanotherapeutics developed thus far have focused primarily on cancer treatment, nanotherapeutics remain to be developed for LN. This Core is built on significant data generated by the teams of Drs. Abdi and Tsokos teams to build nanoimmune therapeutics and their application in LN. The hypothesis of Core B is that targeted delivery of ITs through the newly formed high endothelial venules (HEVs) of the kidneys permits more effective suppression of effector immunity within the kidneys of patients with LN. Furthermore, nanomedicine can reduce the necessary dose of ITs to induce LN remission and thereby reduce their off-target toxicity. Intrarenal inflammation is a defining feature for LN, relying mainly on the homing of immune cells to the kidney. Therefore, the development of kidney-targeted delivery of ITs to suppress intrarenal inflammation is a key unmet clinical need. A major finding in our preliminary data is the development of newly made high HEVs in the LN kidneys. HEVs are specialized veins responsible for the homing of naive T cells that express exclusively a series of glycoproteins on their surfaces known as node addressin (PNAd). Here, we use a well-established nanodelivery strategy in which the surfaces peripheral of nanoparticles are conjugated with a highly specific mAb called MECA79 that recognizes PNAd on the surface of HEVs. Using this highly innovative strategy, we can encapsulate a wide variety of payloads inside the nanoparticles, including immunosuppressive drugs and mAb. Pursuing our data, the main goal of Core B is to synthesize and characterize antibody-conjugated nanocarriers of an inhibitor of CaMK4 and gRNAs (for specific targets such as CaMK4 and IL-23R) (Project 1), and anti-CD3 and anti-IL23 (for Project 2). Core B will work synergistically with both projects to not only synthesize these nanotherapeutics, but also to provide a number of dye-containing nanoparticles for assessment of their trafficking to the kidneys and peripheral tissues. Core B will also...