*Purpose: Here we report a new method to create an artificial and biodegradable matrix of biomimetic nanofibers on single cells with the goal of enhancing CD4⁺CD127^–CD25^highFoxp3⁺ regulatory T cell (Treg) therapies.

*Methods: The nanoscale fibers are composed of self-assembling molecules known as peptide amphiphiles (PAs) which form hydrogels that mimic extracellular matrices. Cell therapies using Tregs have made important clinical progress in the treatment of excessive immune responses, particularly in the amelioration of deleterious responses following organ transplantation. In recent years novel strategies have emerged which aim to enhance cell therapies by coating single cells with a matrix. Matrices formed by PA nanofibers are well established as biocompatible and bioactive materials for cell signaling, targeting, and binding of specific proteins, and we have recently developed strategies to coat them on large numbers of single cells.

*Results: We have optimized a method to coat single Tregs with a layer of PA nanofibers, and found that after this process the cells Tregs remained viable and retained characteristic phenotypic markers of CD3, CD4 and CD25. We also confirmed immunosuppressive functionality of the coated Tregs when compared to uncoated Tregs in mixed lymphocyte reaction inhibition assays. Additionally, coated Tregs continue to bind to extracellular markers of inflammation such as vascular cell adhesion protein 1 (VCAM1). We also modified the nanofiber coating to include a peptide sequence that binds to VCAM1. We found this peptide improved Treg binding to VCAM1 by 36% compared to uncoated Tregs.

*Conclusions: We hypothesize that these novel coatings will allow cells to directly target cells to the inflammatory microenvironment, and seed this niche with anti-inflammatory molecules.

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