Mucoadhesive Nanothalidomide Enema: Simultaneous Radioprotection and Barrier Repair in Radiation Enteritis Therapy

Radiation enteritis, a serious complication arising from abdominopelvic radiotherapy, currently has no effective targeted therapies. Thalidomide (THA), a drug with a complex history, has recently shown promise as an anti-inflammatory and immunomodulatory agent, suggesting therapeutic utility in radiation enteritis. To overcome the challenges of THA's poor aqueous solubility and inefficient drug delivery, we developed carrier-free THA nanoparticles (Nano THA) using a Superstable Pure-nanomedicine Formulation Technology (SPFT). These pure nanocrystals were then incorporated into a hyaluronic acid (HA)-based rectal enema (Nano THA&HA), designed to enhance mucoadhesion and sustain localized drug concentrations at the target site. In a radiation enteritis model, this localized approach minimized systemic exposure while exerting a robust "dual protection" mechanism: (I) direct radioprotection by mitigating DNA damage and mitochondria-mediated apoptosis, and (II) active mucosal barrier repair through the upregulation of tight junction proteins, activation of the Nrf2/HO-1 antioxidant pathway, and the crucial preservation of the Lgr5+ intestinal stem cell niche. Consequently, it ameliorated clinical symptoms, attenuated intestinal fibrosis, and significantly increased survival rates. This work presents a safe and highly effective targeted nanotherapeutic strategy for radiation enteritis, with strong translational potential for the management of radiotherapy-related gastrointestinal toxicity.