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

Guo, Y.; Wang, H.; Cleveland, B.; Leung, H. Y.; Nguyen, D. C.; Smith, J. T.; Gomez Medellin, J. E.; Stewart, G. E.; Johnson, R.; Williams, L. M.; Wang, X.; Qiu, P.; Mustelin, T.; Cao, S.

doi:10.64898/2026.10.13.759006

bioRxiv · 10.64898/2026.10.13.759006

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

Guo, Y.·Wang, H.·Cleveland, B.·Leung, H. Y.·Nguyen, D. C.·Smith, J. T.·Gomez Medellin, J. E.·Stewart, G. E.·Johnson, R.·Williams, L. M.·Wang, X.·Qiu, P.·Mustelin, T.·Cao, S.

View original source ↗Export metadata ↓

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 (pIPANP) by conjugating IPA to a methacrylamide polymer through ester linkages and formulating the polymer into injectable nanoparticles. Following subcutaneous administration of fluorescently-labeled pIPANP, 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 pIPANPs compared to free IPA control at every sampled time point over 14 days. In collagen antibody-induced arthritis (CAIA), pIPANPs reduced clinical disease severity and paw swelling under both prophylaxis and therapeutic administration. pIPANP treatment increased the relative representation of CD11cCD103CD11b- cells with a conventional dendritic cell (cDC)1-associated phenotype and reduced costimulatory-marker frequencies in both CD11cCD103 and CD11cCD11b populations, most prominently in hock-draining lymph nodes. These changes were accompanied by increased PD-1 and IFN-{gamma} 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.

Explore related subjects

bioengineering Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Guo, Y., Wang, H., Cleveland, B., Leung, H. Y., Nguyen, D. C., Smith, J. T., Gomez Medellin, J. E., Stewart, G. E., Johnson, R., Williams, L. M., Wang, X., Qiu, P., Mustelin, T., Cao, S.. 2026-10-16. Indole-3-propionic acid nano-prodrugs sustain increased lymphoid exposure and alleviate experimental autoimmune arthritis. https://doi.org/10.64898/2026.10.13.759006

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Mesoscale Soft Robotics for Mechanically Perturbing and Functionally Monitoring Responses in Human Organoids

Human organoids represent promising models for studies of significance to the biology and medical communities. Of the existing approaches for monitoring organoids, none offers the ability to apply programmable mechanical forces while simultaneously recording multi-modal physiological responses, of relevance to phenomena spanning from traumatic brain injuries to cardiac rhythm disorders. Here, we present a mesoscale soft robotic organoid interface that enables programmable delivery of forces to organoids of diverse shapes, and to map electrophysiological activity and mechanical responses. The platform combines actuation elements with integrated sensors for quantitative measurement and control. Studies using this technology reveal that spheroidal cortical organoids exhibit distinct responses to mechanical trauma, including silencing, recovery, and changes in neuronal firing patterns. Additional experiments on cardiac ring tissues demonstrate that sustained stretching induces beat-to-beat rhythm variability and altered conduction. The results establish a framework for investigating force-triggered transitions between physiological and disease-like states in human tissue models.

bioengineering↗

bioRxiv2026

Few-shot regulatory sequence design with a genomic language model

A central challenge in generative biology is translating knowledge learned from natural sequences and experiments into designs with desired functions. In-context learning (ICL) is an emergent capability of large language models that allows them to adapt to new tasks from a few examples without additional training, enabling these models to become general-purpose learners. Here, we show that the genome language model, Evo 2, exhibits generative ICL in biological sequence design. Prompting with just tens of examples conditions Evo 2 to generate novel and diverse regulatory DNA sequences without any additional training. Mechanistic analysis suggests that genomic ICL may originate from induction, similar to phenomena observed in natural language. Reinforcement learning leveraging sequence-to-function models as experiment-derived rewards further strengthens ICL. We first validate this approach by generating enhancers that drive cell-type-specific gene expression in three human cell lines. Extending this approach in vivo, enhancers designed using human regulatory element data selectively label layer 5 extratelencephalic neurons in the mouse cortex with high specificity and stronger activity than existing enhancers. Our study provides evidence of emergent properties in genomic sequence models and introduces a promising approach for improving functional conditioning in generative biology.

bioengineering↗

bioRxiv2026

IOP-independent treatment for neurodegeneration in glaucoma using optimized ROS-scavenging microparticles for sustained release of erythropoietin

Glaucoma is a slow-progressing neurodegenerative disease of the optic projection to the brain and a leading cause of blindness worldwide. Current treatments are targeted towards lowering intraocular pressure (IOP), the only known, modifiable risk factor; however, this strategy is ineffective in many patients. An early hallmark of glaucomatous neurodegeneration is increased reactive oxygen species (ROS), representing an alternative opportunity for intervention to halt or slow disease progression. In this work, we optimize a ROS-scavenging copolymer, poly(propylene sulfide-co-ethylene sulfide) (PPSES), for formulation of size-controlled, stabilized, antioxidant microparticles (MPs) for sustained release of the protein erythropoietin (EPO). EPO promotes biological antioxidant defense via activation of NRF2-mediated transcription of antioxidant genes. This MP system overcomes the short half-life of EPO and leverages the combined benefits of bioactive EPO with long-lasting, inherently antioxidant PPSES MPs. The lead EPO-MP formulation preserves neurons in both mouse and non-human primate models of glaucoma through suppression of oxidative stress and optic nerve degeneration. EPO-loaded PPSES MPs represent a translationally relevant therapy for long-term management of glaucoma independent of IOP.

bioengineering↗