Immune checkpoint-engineered virus-like particles induce antigen-specific immune tolerance and protect against food allergy.

Recent advances in our understanding of immune tolerance, particularly the role of immune checkpoints in peripheral tolerance, have opened promising new avenues for therapeutic interventions in immune-related disorders. In this study, we developed a novel class of tolerogenic vaccines based on recombinant virus-like particles (tVLPs), engineered to display the immune checkpoint molecule CTLA-4 on their surface and incorporate specific antigens. These tVLPs promote the differentiation of tolerogenic dendritic cells (DCs) in vitro, characterized by a distinct functional phenotype and associated transcriptomic alterations. Furthermore, tVLPs inhibit DC activation and specifically modulate the antigen-specific T cell compartment, inducing a hyporesponsive state in effector T cells while promoting the activation of regulatory T cells (Tregs). The therapeutic efficacy of tVLPs was demonstrated in a murine model of food allergy, where five consecutive daily injections conferred protection against allergic symptoms and anaphylactic shock. Importantly, this effect was antigen-specific, long-lasting, and dependent on Tregs, as evidenced by the transfer of protection to naïve mice following adoptive transfer of Tregs from vaccinated animals. These findings establish tVLPs as a promising platform for the development of targeted immunotherapies for allergies and autoimmune diseases.