Lysophosphatidylserine Nanoparticles Induce Oral Tolerance Independent of TIM-4 and Canonical PS Processing
- 1University at Buffalo
Abstract
Protein replacement therapy is highly effective for treating many protein-deficiency disorders, but its long-term clinical benefit is often limited by anti-drug antibody responses that neutralize therapeutic proteins, compromising safety and efficacy. To address these unwanted immune responses, a lipid nanoparticle-based immunotherapy platform has been developed to induce antigen-specific tolerance. Mice treated with antigen associated with either double-chain phosphatidylserine (PS) or lysophosphatidylserine (LysoPS), a single-acyl-chain phospholipid, showed reduced antibody titers following subcutaneous pre-exposure. However, only LysoPS nanoparticles induced tolerance after oral administration, suggesting structural differences between PS and LysoPS can impact tolerogenic potential, depending on the site of delivery. As an apoptotic "eat-me" signal, PS is recognized by phagocytic receptors such as TIM-4 and is associated with LC3-associated phagocytosis. These nanoparticles have been hypothesized to promote apoptotic mimicry to regulate immunity. However, the contribution of TIM-4 to oral tolerance remains unclear. Here, we investigated the role of TIM-4 in LysoPS-mediated oral tolerance using a knockout mouse model. Our data showed that TIM-4-/- mice induced tolerance to ovalbumin encapsulated in LysoPS comparable to that of wild-type mice. We also found that LysoPS nanoparticles did not follow the same surface engagement and intracellular trafficking pathways as PS nanoparticles. These results reveal that, despite sharing the same headgroup, differences in acyl chain number critically shape nanoparticle-immune cell interactions and provide a mechanistic framework that may explain the unique ability of LysoPS nanoparticles to induce oral tolerance.
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BibTeX
@misc{ovalle2026lysophosphatidylserine,
title = {{Lysophosphatidylserine Nanoparticles Induce Oral Tolerance Independent of TIM-4 and Canonical PS Processing}},
author = {E. J. Ovalle and V. Chak and E. Wohlfert and S. Balu-Iyer and J. G. Kay},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.24.754158},
url = {https://www.biorxiv.org/content/10.64898/2026.09.24.754158v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Lysophosphatidylserine Nanoparticles Induce Oral Tolerance Independent of TIM-4 and Canonical PS Processing
AU - E. J. Ovalle
AU - V. Chak
AU - E. Wohlfert
AU - S. Balu-Iyer
AU - J. G. Kay
PY - 2026
DA - 2026/09/24
PB - bioRxiv
DO - 10.64898/2026.09.24.754158
UR - https://www.biorxiv.org/content/10.64898/2026.09.24.754158v1
AB - Protein replacement therapy is highly effective for treating many protein-deficiency disorders, but its long-term clinical benefit is often limited by anti-drug antibody responses that neutralize therapeutic proteins, compromising safety and efficacy. To address these unwanted immune responses, a lipid nanoparticle-based immunotherapy platform has been developed to induce antigen-specific tolerance. Mice treated with antigen associated with either double-chain phosphatidylserine (PS) or lysophosphatidylserine (LysoPS), a single-acyl-chain phospholipid, showed reduced antibody titers following subcutaneous pre-exposure. However, only LysoPS nanoparticles induced tolerance after oral administration, suggesting structural differences between PS and LysoPS can impact tolerogenic potential, depending on the site of delivery. As an apoptotic "eat-me" signal, PS is recognized by phagocytic receptors such as TIM-4 and is associated with LC3-associated phagocytosis. These nanoparticles have been hypothesized to promote apoptotic mimicry to regulate immunity. However, the contribution of TIM-4 to oral tolerance remains unclear. Here, we investigated the role of TIM-4 in LysoPS-mediated oral tolerance using a knockout mouse model. Our data showed that TIM-4-/- mice induced tolerance to ovalbumin encapsulated in LysoPS comparable to that of wild-type mice. We also found that LysoPS nanoparticles did not follow the same surface engagement and intracellular trafficking pathways as PS nanoparticles. These results reveal that, despite sharing the same headgroup, differences in acyl chain number critically shape nanoparticle-immune cell interactions and provide a mechanistic framework that may explain the unique ability of LysoPS nanoparticles to induce oral tolerance.
ER -