Butyrate—a metabolite produced by commensal bacteria—has been extensively studied for its immunomodulatory effects on immune cells, including regulatory T cells, macrophages and dendritic cells. However, the development of butyrate as a drug has been hindered by butyrate’s poor oral bioavailability, owing to its rapid metabolism in the gut, its low potency (hence, necessitating high dosing), and its foul smell and taste. Here we report that the oral bioavailability of butyrate can be increased by esterifying it to serine, an amino acid transporter that aids the escape of the resulting odourless and tasteless prodrug (O-butyryl-l-serine, which we named SerBut) from the gut, enhancing its systemic uptake. In mice with collagen-antibody-induced arthritis (a model of rheumatoid arthritis) and with experimental autoimmune encephalomyelitis (a model of multiple sclerosis), we show that SerBut substantially ameliorated disease severity, modulated key immune cell populations systemically and in disease-associated tissues, and reduced inflammatory responses without compromising the global immune response to vaccination. SerBut may become a promising therapeutic for autoimmune and inflammatory diseases.

Targeted nanocarriers deliver HIV-1 latency-reversing agents to CD4 ⁺ T cells in the lymph nodes.

The COVID-19 pandemic underscores the need for rapid, safe, and effective vaccines. In contrast to some traditional vaccines, nanoparticle-based subunit vaccines are particularly efficient in trafficking antigens to lymph nodes, where they induce potent immune cell activation. Here, we developed a strategy to decorate the surface of oxidation-sensitive polymersomes with multiple copies of the SARS-CoV-2 spike protein receptor-binding domain (RBD) to mimic the physical form of a virus particle. We evaluated the vaccination efficacy of these surface-decorated polymersomes (RBD_surf) in mice compared to RBD-encapsulated polymersomes (RBD_encap) and unformulated RBD (RBD_free), using monophosphoryl-lipid-A-encapsulated polymersomes (MPLA PS) as an adjuvant. While all three groups produced high titers of RBD-specific IgG, only RBD_surf elicited a neutralizing antibody response to SARS-CoV-2 comparable to that of human convalescent plasma. Moreover, RBD_surf was the only group to significantly increase the proportion of RBD-specific germinal center B cells in the vaccination-site draining lymph nodes. Both RBD_surf and RBD_encap drove similarly robust CD4⁺ and CD8⁺ T cell responses that produced multiple Th1-type cytokines. We conclude that a multivalent surface display of spike RBD on polymersomes promotes a potent neutralizing antibody response to SARS-CoV-2, while both antigen formulations promote robust T cell immunity.

Monoclonal antibodies and peptides are conjugated to the surface of nanocarriers (NCs) for targeting purposes in numerous applications. However, targeting efficacy may vary with their specificity, affinity, or avidity when linked to NCs. The physicochemical properties of NCs may also affect targeting. We compared the targeting efficacy of the CD4 binding peptide BP4 and an anti‐CD4 monoclonal antibody (CD4 mAb) and its fragments, when conjugated to lipid‐coated poly(lactic‐co‐glycolic) acid nanoparticles (LCNPs). Negatively charged LCNPs with cholesteryl butyrate in the lipid layer (cbLCNPs) dramatically reduced nonspecific binding, leading to higher targeting specificity, compared to neutral or positively charged LCNPs with DOTAP (dtLCNP). cbLCNPs surface conjugated with a CD4 antibody (CD4‐cbLCNPs) or its fragments (fCD4‐cbLCNPs), but not BP4, showed high binding in vitro to the human T cell line 174xCEM, and preferential binding to CD3+ CD14‐CD8‐ cells from pigtail macaque peripheral blood mononuclear cells. CD4‐cbLCNPs showed 10‐fold higher binding specificity for CD4+ than CD8+ T cells, while fCD4‐cbLCNPs demonstrated the highest binding level overall, but only three‐fold higher binding specificity. This study demonstrates the importance of ζ‐potential on NC targeting and indicates that CD4 mAb and its fragments are the best candidates for delivery of therapeutic agents to CD4+ T cells. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1177–1188, 2018.