Lymph node-targeted long-acting butyrate micelles induce regulatory immune modulation

Abstract Regulatory T cells (Tregs) play essential roles in maintaining immune homeostasis and preventing autoimmunity and allergy. Peripherally derived Tregs are induced most efficiently in the lymph nodes (LNs), yet current therapies are not effectively delivered to these sites. The short-chain fatty acid butyrate facilitates extrathymic differentiation of Tregs and has been considered a promising therapeutic candidate. However, there are challenges to its use, including its foul odor, quick metabolism, and low efficiency with traditional oral delivery. Herein, we designed butyrate-prodrug micelles that deliver butyrate to peripheral LNs through subcutaneous (SC) administration. We have developed two polymeric micelles, one with a neutral charge (termed NtL-ButM) and one with a negative charge (termed Neg-ButM), which both contain 28 wt% butyrate and have similar sizes of ~40 nm. In a biodistribution study, we observed that Neg-ButM, not NtL-ButM, accumulated in draining LNs for over one month. At the cellular level, the Neg-ButM were taken up mostly by the macrophages and dendritic cells in the LNs and inhibited LPS-induced activation of those cells. In antibiotic-treated mice, three weekly doses of Neg-ButM significantly increased the numbers of CD25+ Foxp3+ CD4+ Tregs in draining LNs compared to either PBS or NtL-ButM treatment. Furthermore, we demonstrated that, when combined with intragastrically administered peanut proteins, the SC-injected Neg-ButM protected from anaphylactic responses in a mouse model of peanut allergy. This approach provides a potential Treg-based therapy against food allergies. Supported by a seed grant from the Chicago Immunoengineering Innovation Center of the University of Chicago.