PROJECT SUMMARY Systemic lupus erythematosus (SLE) is a multisystem autoimmune disorder characterized by a loss of tolerance to multiple endogenous antigens, for which there is no cure. Current therapeutic options for SLE patients involve a variety of non-specific immunosuppressive or anti-inflammatory agents that have significant associated side effects and are often inadequate. There is thus a great unmet need to develop curative therapies for this disease. In SLE, tissue injury is often mediated by aberrant expression of immunoregulatory signaling proteins. In particular, Src homology region 2 domain-containing phosphatase-2 (SHP-2) has been shown to enhance disease-active T cell proliferation and promote downstream cytokine production, each of which are innately tied to the pathophysiology of the disease. The importance of this phosphatase in the promotion of SLE has been further demonstrated by its inhibition, wherein systemic treatment normalized many of the symptoms of the disease concomitant with an extension of lifespan. Yet, SHP-2 is expressed throughout the body, thus the potential for off-target effects from systemic therapies is great. The spleen is the largest secondary lymphoid organ and an active regulator of the immune response, with a structure designed to increase the likelihood of rare interactions between cells, in particular cognate lymphocytes and antigen-presenting cells. While the spleen is not considered a target organ in SLE, it is an active site for autoantibody generation and the accumulation of pathogenic cells, including DNTCs, which are trafficked throughout the body to elicit the observed multi-organ damage. We thus hypothesize that the localization of therapeutics to the spleen, in particular modulators of SHP-2, may be sufficient to enable a systemic therapeutic effect. To accomplish this, we propose to utilize engineered senescent red blood cell mimetic nanohybrids to specifically deliver small molecule inhibitors or oligonucleotide-based therapeutics to the splenic milieu. If successful, the generated materials may potentiate the discovery of novel therapeutic options for the treatment of SLE with the capacity for increased specificity and decreased side effects.