Many current autoimmune disease therapies act through nonspecific suppression of the immune response, resulting in global immunosuppression and deleterious off-target effects. Antigen-specific immunotherapies that target and suppress only offending autoreactive immune cells to restore autoantigenic tolerance would address a pressing need for safer and more effective therapies, yet remain elusive. Endogenous mechanisms for maintaining immunological tolerance and homeostasis suggest however that restoration of immune tolerance is plausible. For example, mucosal tolerance against ingested antigens is maintained through mechanisms of oral tolerance, where antigens are taken up, processed, and presented in gut-associated lymphoid tissues (GALT) in a highly tolerogenic context. Peripheral tolerance is maintained primarily through a state of antigen unresponsiveness called anergy which occurs when lymphocytes (B or T cells) mount an initial response to primary antigenic signal but do not receive sufficient secondary costimulatory signals to sustain activation. B cells in particular, which contribute to autoimmune pathogenesis through antigen presentation and effector functions, have potential for direct antigen-specific targeting through the B cell receptor (BCR) and provide a promising target for tolerogenic immunotherapies. Multivalent nanomaterials (such as soluble antigen arrays, or cSAgAs) that present multiple copies of covalently-conjugated autoantigen can be tailored to induce anergy in autoimmune B cells through high avidity binding of the BCR in the absence of costimulatory signals to modulate BCR signaling. Design and development of effective cell-targeted antigen-specific immunotherapies should take into account appropriate physicochemical properties of delivered antigen in light of known molecular, cellular, and transport mechanisms for inducing peripheral tolerance. This project seeks to build upon endogenous mechanisms of tolerance to design targeted antigen-specific immunotherapies to treat autoimmune diseases.