Background

Inflammatory bowel disease (IBD), represented by Crohn's disease and ulcerative colitis, is a refractory condition characterized by persistent chronic inflammation of the intestinal tract. Patients often suffer from frequent relapses, abdominal pain, and bloody stools, and many require lifelong medication. Currently, corticosteroids, biologics, and immunosuppressants are primarily prescribed in clinical practice to suppress symptoms. However, these agents are prone to causing serious toxicity, such as systemic immunosuppression, decreased bone mineral density, and increased risk of infection, when administered long-term. This is because it fails to act selectively only on the lesion site and instead spreads throughout the body via the bloodstream.

Existing small molecule compounds and antibody therapies focus on blocking excessively secreted inflammatory proteins, which has limitations in fundamentally restoring the damaged mucosal environment. Messenger RNA (mRNA) technology, which directly synthesizes target proteins within the body, has gained attention as an alternative for actively restoring mucosal healing and immune homeostasis. However, it has been difficult to deliver genetic material intact into the cells of colonic lesions via oral or intravenous routes, due to the harsh digestive enzyme environment of the gastrointestinal tract and the thick mucus barrier. Therefore, there was an urgent need to develop a high-efficiency local delivery vehicle that can deliver mRNA specifically to the inflamed intestinal mucosa while reducing liver toxicity.

Key Findings

Researchers focused on the glucocorticoid skeleton itself, which possesses anti-inflammatory properties, to synthesize new ionizable lipids and produce lipid nanoparticles (LNPs). Among the synthesized compounds, MP2 LNP, produced based on a methylprednisolone-derived lipid, was selected as the optimal lead formulation. The MP2 formulation was designed to penetrate deep into the epithelium and submucosa of the inflammatory site when administered locally into the intestinal tract via the rectum.

In vivo evaluation results demonstrated that the delivery efficiency of MP2 LNPs was 15-fold higher than that of SM-102 LNPs used in FDA-approved COVID-19 vaccines. The researchers encapsulated interleukin-35 (IL-35) mRNA, a cytokine with powerful immunosuppressive and inflammatory regulatory functions, into MP2 particles and administered them to animal models. When MP2-IL-35 was locally injected rectally into mouse models of acute and chronic colitis induced by dextran sulfate sodium (DSS), the disease activity index and histological scores significantly improved. The colon length, which had shortened due to inflammation, was preserved at normal levels, and levels of pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), plummeted.

Consistent therapeutic responses were also observed in validation using patient tissues. In experiments where human colonic biopsy samples collected via colonoscopy were cultured ex vivo, MP2 LNPs efficiently delivered mRNA to immune cells, epithelial cells, and vascular endothelial cells throughout the mucosal tissue. Treatment of MP2-IL-35 in tissues derived from patients with actual inflammatory bowel disease reduced the population of effector T cells that drive tissue destruction and increased the proportion of regulatory T cells (Tregs) that maintain immune balance, thereby reshaping the abnormal immune environment.

Significance and Outlook

This study is original in that it transformed steroid agents, whose long-term use was limited due to systemic side effects, into safe drug delivery vehicles by modifying their structure. It overcame the delivery limitation of existing intravenous LNP formulations, which predominantly accumulated in the liver, by accurately targeting the lesion site via rectal administration. It demonstrated that a continuous anti-inflammatory microenvironment can be created by enabling intestinal mucosal cells to directly express the immunosuppressive protein IL-35.

Before actual clinical application, a precise process must be established and long-term safety verified. Compared to mouse models, detailed pharmacokinetic analysis is required to determine how uniformly rectal enema or suppository formulations act in the human large intestine environment, which features thicker barriers and higher mucus secretion. Because the depth of mucosal ulcers and the distribution of gut microbiota vary among patients with colitis, follow-up studies are essential to further evaluate the reproducibility of lesion penetration. Mass production in the manufacturing process and ensuring storage stability are also cited as major challenges at the commercialization stage.