Tackling TNF-α in autoinflammatory disorders and autoimmune diseases: From conventional to cutting edge in biologics and RNA- based nanomedicines

Autoinflammatory disorders and autoimmune diseases result from abnormal deviations of innate and adaptive immunity that heterogeneously affect organs and clinical phenotypes. Despite having etiologic and phenotypic differences, these two conditions share the onset of an aberrant inflammatory process. Targeting the main drivers controlling inflammation is useful to treat both autoimmune and autoinflammatory syndromes. TNF-alpha is a major player in the inflammatory immune response, and anti-TNF-alpha antibodies have been a revolutionary treatment in many autoimmune disorders. However, production difficulties and high development costs hinder their imple-mentation, and accessibility to their use is still limited. Innovative strategies aimed at overcoming the limitations associated with anti-TNF-alpha antibodies are being explored, including RNA-based therapies.Here we summarize the central role of TNF-alpha in immune disorders and how anti-TNF-based immunotherapies changed the therapeutic landscape, albeit with important limitations related to side effects, tolerance, and resistance to therapies. We then outline how nanotechnology has provided the final momentum for the use of nucleic acids in the treatment of autoimmune and autoinflammatory diseases, with a focus on inflammatory bowel diseases (IBDs). The example of IBDs allows the evaluation and discussion of the nucleic acids-based treatments that have been developed, to identify the role that innovative approaches possess in view of the treatment of autoinflammatory disorders and autoimmune diseases.