Researchers have been working on the idea of inverse vaccines for decades, exploring various methods for delivering the vaccine targets -antigens -without provoking an immune response. Attempts to develop peptide-based tolerogenic vaccinations against rheumatoid arthritis and systemic lupus erythematosus date almost twenty years ago. However, by now the research has been based on animal models only, while data from clinical studies is still not available. A clinical trial to test a tolerogenic DNA vaccine in patients with multiple sclerosis has been performed nearly 15 years ago. The vaccine was generally successful, but the efficiency was not higher than the drugs available on the market, in order to get approval. The development of a tolerogenic mRNA vaccine able to restrict symptoms in several mouse models of multiple sclerosis has been reported in 2021. The researchers achieved this by using modified mRNA encoding a self-antigen delivered by a non-inflammatory lipoplex carrier, which resulted in diminishing the autoimmunity through the activation of antigen-specific regulatory T cells. Recent breakthrough A breakthrough results have been reported last year on developing a technique that involves attaching a glycosylated polymer to an antigen, which directs it to the liver. The liver is crucial for establishing immune tolerance. Because of its distinctive blood supply, the liver exhibits a prominent local immune tolerogenic microenvironment. The network of hepatic regulatory immune cells is an important mechanism underlying liver immune tolerance. Multiple types of liver-resident antigen-presenting cells play immune regulatory function, and are also able to induce differentiation of circulating immune cells into regulatory cells to extend systemic tolerance. How does it work: