Nanoparticles targeting liver sinusoidal endothelial cells improve AAV gene transfer and promote tolerance-spreading to capsid and transgene epitopes

Trophic Communications — Tue, 09 Jun 2026 14:13:19 +0000

Nanoparticles targeting liver sinusoidal endothelial cells improve AAV gene transfer and promote tolerance-spreading to capsid and transgene epitopes

Presented by Sabine Fleischer at the 19th International Congress on Immunology Vienna 2025

Authors: R.Hardet, M.Blandin, S.-H.Wang, R.Digigow, C.Gottwick, M.Heine, L.M.Marques Mesquita, M.Fanzutti, A.-L.Vocaturo, D.Mungalpara, O.Boyer, S.Fleischer, S.Adriouch

Summary

Introduction: Adeno-associated viral (AAV) gene transfer is still impeded by deleterious immune responses against capsid- and transgene-derived antigens. We developed an innovative approach for inducing antigen-specific tolerance to tackle these limitations. For that, nanoparticle-carriers were designed to preferentially deliver antigenic peptides to liver sinusoidal endothelial cells (LSECs) exploiting their natural potential of cross-presenting antigens and tolerizing T cell responses.
Objectives: Different mouse models of AAV-mediated gene transfer to muscle and liver were used to assess whether nanoparticles coupled to capsid- and transgene-derived peptides can effectively inhibit vector- and transgene-specific immune responses and improve transgene persistence.
Methods: Nanoparticle-peptide-carriers were intravenously administered at predefined timepoints in the context of muscle- and liver-directed AAV-gene transfer. T- and B-cell responses were analysed by ELISpot, flow cytometry, and ELISA; transgene expression by qPCR. Non-parametric Mann-Whitney test and one-way ANOVA were used to compare differences between two or multiple groups, respectively.
Results: LSEC-targeting nanoparticle-peptide-carriers abrogated CD4+ and CD8+ T cell immune responses towards the targeted peptide-epitopes and significantly improved transgene persistence in liver and muscle. Furthermore, nanoparticles carrying a single peptide-epitope recognized by anti-transgene CD8+ T cells also induced tolerance in CD8+ and CD4+ T cells specific for other transgene- and capsid-derived peptide-epitopes. This remarkable extension of tolerance, which combines linked suppression and infectious tolerance, is reported here for the first time and termed tolerance-spreading (Tspread). Importantly, Tspread remained restricted to the antigens carried by the AAV vectors and did not impair concurrent vaccination against an unrelated third-party tumour antigen.
Conclusion: Reported for the first time in immunotherapy, nanoparticle-peptide-carriers targeting LSECs induce Tspread to other relevant capsid- and transgene-derived epitopes, which is beneficial for achieving robust and durable tolerance in vivo. This finding is of great clinical importance, offering a novel antigen-specific strategy to improve viral vector-mediated gene transfer.

Antigen-specific immune modulation with liver-targeting nanoparticles fosters immune protective regulatory T cells to delay Type 1 Diabetes

Trophic Communications — Tue, 19 May 2026 18:03:46 +0000

Antigen-specific immune modulation with liver-targeting nanoparticles fosters immune protective regulatory T cells to delay Type 1 Diabetes

Poster Helmholtz Munich

Authors: Isabelle Serr, Daria Krzikalla, Barbara Metzler, Sabine Fleischer, Carolin Daniel

Summary

Type 1 Diabetes (T1D) is characterized by the loss of immune tolerance to beta-cells in the pancreas, resulting in their immune-mediated destruction. Restoring antigen-specific immune tolerance, thereby circumventing critical side effects of non-specific immunosuppression is a long-awaited goal for the prevention of T1D. We tested peptideconjugated nanoparticles developed by Topas Therapeutics that leverage the tolerogenic capacity of liver sinusoidal endothelial cells (LSECs) to restore antigen-specific immune tolerance in T1D

Scientific Poster – Topas Therapeutics

Nanoparticles targeting liver sinusoidal endothelial cells improve AAV gene transfer and promote tolerance-spreading to capsid and transgene epitopes