Hierarchically Assembled Curcumin-Vitamin E-Zinc Thermo-Gel for Multi-Synergistic Prevention and Treatment of Radiation-Induced Oral Mucositis

Radiation-induced oral mucositis (RIOM) substantially compromises the efficacy of cancer treatment and patient survival, while current therapeutic approaches exhibit limited efficacy in addressing its multifactorial pathogenesis. Curcumin possesses multi-targeted pharmacological properties relevant to RIOM, including antioxidative, anti-inflammatory, and mucosal repair effects, rendering it an ideal therapeutic agent. This study developed a curcumin-based intelligent-responsive integrated therapeutic platform (Cur-VE-Zn@gel) via a hierarchical assembly strategy. Specifically, curcumin was covalently bound to vitamin E to form the active center, while its coordination with Zn 2+ facilitates self-assembly into stable polymeric structures. This design not only significantly enhanced the biosecurity of curcumin but also amplified its antioxidant, anti-inflammatory, and tissue repair capabilities, while exhibited stable DNA repair characteristics, thus establishing a comprehensive radioprotective barrier. This bioactive complex was further incorporated into an adhesive thermosensitive hydrogel consisting of chitosan and poloxamer, which enabled targeted delivery to oral mucosa and bypassed the low systemic bioavailability of curcumin. Comprehensive in vitro and in vivo evaluations demonstrated that the Cur-VE-Zn@gel platform effectively modulated DNA damage repair, oxidative stress, inflammatory cascades, and epithelial regeneration, thereby achieving synergistic multi-targeted therapy for the suppression of RIOM. Ultimately, this biomaterial-based strategy successfully addresses the key pharmacological limitations of curcumin through structural modification and targeted delivery, providing a highly promising, safe, and effective approach for the clinically challenging management of RIOM.