Work

Indole-3-propionic acid nano-prodrugs sustain increased lymphoid exposure and alleviate experimental autoimmune arthritis

Year: 2026

Type: preprint

Abstract: Chronic inflammatory diseases, including rheumatoid arthritis (RA), currently require sustained control of inflammation. Although long-acting therapies can reduce dosing frequency, those that rely on systemic immunosuppression may still compromise protective immunity. Microbiota-derived metabolites offer a complementary starting point for immune modulation through naturally occurring host–microbe signals. Indole-3-propionic acid (IPA), a gut microbial tryptophan metabolite naturally present in human circulation, has newly recognized immunoregulatory activity, yet its effects across disease contexts and its potential for therapeutic use remain incompletely defined. Here, we developed polymeric IPA nano-prodrugs (pIPA NP ) by conjugating IPA to a methacrylamide polymer through ester linkages and formulating the polymer into injectable nanoparticles. Following subcutaneous administration of fluorescently-labeled pIPA NP , injection-site fluorescence remained detectable for at least 35 days, with labeled material detected in multiple lymph nodes. LC-MS/MS confirmed higher lymph-node IPA concentrations in mice treated with the pIPA NP s compared to free IPA control at every sampled time point over 14 days. In collagen antibody-induced arthritis (CAIA), pIPA NP s reduced clinical disease severity and paw swelling under both prophylaxis and therapeutic administration. pIPA NP treatment increased the relative representation of CD11c⁺CD103⁺CD11b⁻ cells with a conventional dendritic cell (cDC)1-associated phenotype and reduced costimulatory-marker frequencies in both CD11c⁺CD103⁺ and CD11c⁺CD11b⁺ populations, most prominently in hock-draining lymph nodes. These changes were accompanied by increased PD-1⁺ and IFN-γ⁺ frequencies among CD4⁺ and CD8⁺ T cells. Fluorescent nanoparticle tracking showed preferential association with several myeloid populations, while single-cell profiling revealed divergent interferon-response signatures across splenic populations. These findings reveal arthritis-associated immunomodulatory activity of polymeric IPA and support its further development as a microbiome-inspired, long-acting approach to inflammatory arthritis.

Source: bioRxiv (Cold Spring Harbor Laboratory)

DOI: 10.64898/2026.10.13.759006