Researchers developed a nanoparticle platform for a novel lipid-based immunotherapy that aims to prevent undesirable immune responses against therapeutic proteins, such as the recombinant factor VIII (FVIII) in patients with hemophilia type A (HA).

“In the case of HA, a bleeding disorder, about one third of the severe HA patients receiving replacement therapy using recombinant FVIII develop neutralizing anti-FVIII antibodies, referred to as inhibitors, that abrogate the biological activity and hemostatic efficacy of the administered FVIII,” the study authors explained.

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The approach designed by Nguyen et al enables the pre-exposure of proteins in the presence of lysophosphatidylserine derivative-containing nanoparticles, thereby allowing individuals to develop immune tolerance toward that protein prior to therapy initiation. This prevents immunogenicity upon subsequent protein-based treatments.

“As the risk of antidrug antibody development is much higher during the first 20 exposures of replacement therapy for conditions such as HA, this approach can supplement replacement therapy during initial exposures to effectively prevent inhibitory titers and subsequent clinical complications,” the authors stated.

Moreover, these nanoparticles are administered orally. Hence, they can be easily introduced into clinical practice after proper validation. In addition, this administration route allows for the exposure of formulations to the mucosal immune system, an important tolerogenic site. The oral administration of phosphatidylserine has been already used in other contexts, including to reduce the risk of dementia in older individuals.

Mechanistically, Nguyen et al showed that the nanoparticles were stable in the gastrointestinal tract and that their cargoes could be recognized and processed by several populations of T-cell immunoglobulin and mucin domain containing 4 (TIM-4)-expressing immune cells to induce effective oral tolerance.


Nguyen NH, Glassman FY, Dingman RK, et al. Rational design of a nanoparticle platform for oral prophylactic immunotherapy to prevent immunogenicity of therapeutic proteins. Sci Rep. 2021;11(1):17853. doi:10.1038/s41598-021-97333-0