# Colon-targeted microbiota-modulating nanoparticles amplify azathioprine efficacy via gut microbiota axis remodeling in inflammatory bowel disease

## TL;DR

A new nanoparticle improves azathioprine's effectiveness in treating inflammatory bowel disease by targeting the gut microbiota.

## Contribution

A colon-targeted nanoparticle enhances azathioprine efficacy by modulating gut microbiota and improving intestinal barrier repair.

## Key findings

- APZE nanoparticles increased azathioprine's oral bioavailability and colonic accumulation in rats.
- APZE reduced inflammation and repaired the intestinal barrier in IBD mouse models.
- Combining APZE with Bifidobacterium improved colitis outcomes and microbiota balance.

## Abstract

Inflammatory bowel disease (IBD) is characterized by destruction of the intestinal barrier, dysregulation of mucosal immunity, and imbalance of the gut microbiota homeostasis. Conventional immunosuppressants such as azathioprine (AZA), commonly used in the treatment of IBD, can partially alleviate symptoms but fail to restore normal barrier and immune functions, while exhibiting non-negligible adverse effects. Here, we report an AZA-loaded microbiota-modulating and colon-targeted nanoparticle constructed from pectin, Zein, and Eudragit®S100 (APZE).

APZE could effectively encapsulate AZA and enhance its cellular and intestinal uptake, thereby improving oral bioavailability in rats compared to AZA suspension. Additionally, its colon targeting ability and mucoadhesive properties prolonged colonic retention, leading to higher colonic accumulation, as indicated by the AUC of colon fluorescence intensity in rats after oral administration of the DiR-labeled formulation. Animal studies demonstrated that APZE significantly reduced inflammation in IBD mice, repaired the intestinal barrier, modulated the gut microbiota, and upregulated short-chain fatty acid levels, exhibiting significant therapeutic efficacy with good safety. The protective effect of APZE against colitis is largely microbiota-dependent. When co-administered with commercially available Bifidobacterium, APZE attenuated colitis effectively, demonstrating excellent therapeutic effects and favorable safety.

In summary, our findings indicate that APZE and Bifidobacterium improved intestinal barrier repair and colitis-related outcomes in a DSS-induced model, supporting their potential as therapeutic agents for IBD.

The online version contains supplementary material available at 10.1186/s12951-026-04136-4.