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bioRxiv · 10.64898/2026.05.18.725807

Modular mRNA platform for in vivo antigen-specific immune tolerance

Imai, S.·Nishida, N.·Maeno, R.·Ikebuchi, A.·Sasatsuki, H.·Saito, R.·Matoba, K.·Iwabuchi, S.·Iba, T.·Naito, H.·Nagamori, K.·Le, T. V.·Fujitsuka, I.·Ueda, M.·Hanayama, R.·Yamano, T.
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Abstract

Immune-mediated diseases such as autoimmunity and allergy arise from dysregulated antigen-specific responses, yet current therapies largely rely on broad immunosuppression and rarely re-establish durable, antigen-selective tolerance. Here we introduce Tol-mRNA, a modular tolerogenic mRNA platform designed to deliver multiple immune-regulatory signals in vivo to program antigen-specific tolerance. Tol-mRNA co-encodes an antigen together with two complementary regulatory cues, PD-L1 and TGF-{beta}, enabling coordinated antigen presentation and tolerogenic signaling that robustly induces antigen-specific Tregs and suppresses pathogenic effector responses. In murine disease models, Tol-mRNA conferred therapeutic benefit across distinct immune pathologies. In experimental autoimmune encephalomyelitis, Tol-mRNA ameliorated clinical disease and reduced inflammatory immune activation. In an ovalbumin-driven food allergy model, Tol-mRNA prevented allergic symptoms and dampened type 2 inflammation. Extending these findings to humans, Tol-mRNA demonstrated potent, antigen-dependent immunosuppressive activity and a strong capacity to promote antigen-specific Treg induction in human immune settings. Collectively, these results establish Tol-mRNA as a scalable and versatile approach to reprogram antigen-specific immunity and support its development as a next-generation therapeutic modality for immune-mediated diseases.

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Imai, S., Nishida, N., Maeno, R., Ikebuchi, A., Sasatsuki, H., Saito, R., Matoba, K., Iwabuchi, S., Iba, T., Naito, H., Nagamori, K., Le, T. V., Fujitsuka, I., Ueda, M., Hanayama, R., Yamano, T.. 2026-05-21. Modular mRNA platform for in vivo antigen-specific immune tolerance. https://doi.org/10.64898/2026.05.18.725807

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