Targeting autoimmunity in Rheumatoid Arthritis with nanoparticles displaying Liprin-1 peptide

Abstract Nanoparticle-based strategies offer a promising tool for inducing antigen-specific immune tolerance across various autoimmune conditions, by acting as master switch to turn-off the autoimmune response. Building on our previous work demonstrating the therapeutic potential of plant-made nanoparticles in rheumatoid arthritis, we present a systematic evaluation of key parameters—including dosing regimen, route of administration, and immunization schedule—to optimize both efficacy and safety. We developed virus-based nanomaterials expressing Tomato Bushy Stunt Virus (TBSV) nanoparticles engineered to display the immunodominant Liprin-1 peptide in the Nicotiana benthamiana plant platform. The mechanisms responsible for the observed protective effects against rheumatoid arthritis were also investigated. Our findings highlight the critical role of repeated intravenous administration and precise dosing in promoting regulatory T cell (Treg) induction and cytokine modulation. Furthermore, we dissected the individual contributions of the Liprin-1 peptide and the viral capsid scaffold in driving immune tolerance. These results support the potential of plant-derived nanoparticles as a versatile and effective platform for antigen-specific immunotherapy, with rheumatoid arthritis serving as a proof-of-concept model for broader applications in the field of autoimmunity. One Sentence Summary Plant-made nanomaterials induce tolerance in arthritis models via repeated IV dosing, triggering an antigen-specific regulatory immune response. Competing Interest Statement LA and RZ were founders of Dimante SB srl. AR, EG and RZ are employees of Diamante SB srl. The work here described has been patented. AM, JM, JB, NS and SF are part of the scientific advisory board of Diamante SB srl. The remaining author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Footnotes This version of the manuscript has been revised by re-writing the discussion and changing the order too the results section