Engineered extracellular vesicles for oral delivery of anti-fibrotic therapies

Overview

This technology addresses a critical delivery challenge in treating fibrostenotic Crohn's disease by using engineered extracellular vesicles (EVs) to orally deliver anti-fibrotic nucleic acid therapies (NATs) directly to activated fibroblasts and macrophages in fibrotic intestinal tissue. Current parenteral administration of NATs such as antisense oligonucleotides and siRNA leads to systemic exposure, accumulation in non-target organs, and insufficient delivery to diseased tissue. The proposed solution exploits EVs' natural ability to carry macromolecules across the intestinal epithelium, enabling targeted oral delivery via a commercially available colon-targeted dosage form.

Technical specifications

• EV sources: Mesenchymal stem cell (MSC) exosomes and bovine milk EVs, both naturally capable of traversing the intestinal epithelium and possessing mucosal healing properties
• Cargo loading: Non-destructive methods (avoiding electroporation) for loading microRNAs, siRNAs, and mRNAs into EVs with high efficiency, using fusion with drug-loaded liposomes via freeze-thaw and/or microfluidics approaches
• Target NATs: Anti-fibrotic agents including antisense oligos targeting SMAD7 and/or NF-kappa B, and α7-integrin siRNA
• Validated transport: Demonstrated >5% of applied dose crosses Caco-2 monolayers and intestinal organoid monolayers derived from IBD patient tissue
• Anti-inflammatory effect: MSC exosomes cross Caco-2 monolayers and attenuate inflammation in LPS-inflamed macrophages in co-culture models
• Stability: Engineered exosomes remain stable in simulated intestinal fluids
• Enhanced therapeutic effect: Cargo manipulation significantly boosts inherent mucosal healing and anti-fibrotic properties of native EVs

Technology readiness level

The technology is at an advanced preclinical stage with key aspects already validated. In vitro transport across intestinal epithelium has been confirmed using Caco-2 mono- and co-culture systems as well as patient-derived intestinal organoid monolayers. Anti-inflammatory activity has been demonstrated in co-culture models with inflamed macrophages, and EV stability in the gut environment has been established. Unique nucleic acid loading capabilities have been developed and optimized. Future validation will include engineering EVs with specific anti-fibrotic NATs, characterizing NAT-loaded EVs, testing epithelial transport against native counterparts, and evaluating therapeutic potential in established co-culture models and a new intestinal fibrosis model using primary human colonic fibroblasts.