Mechanistic Study of Ion-Exchange Strategy for Regulating Multi-Metal Homeostasis to Ameliorate Mitochondrial Dysfunction in Radiation-Induced Oral Mucositis

Radiation-induced oral mucositis (RIOM) is a common and severe complication of radiotherapy for head and neck cancers. Preliminary studies by the applicant revealed that RIOM is not merely characterized by isolated iron overload, but rather exhibits a novel pathological feature of multi-metal dyshomeostasis, specifically "iron overload accompanied by zinc/magnesium depletion." Accordingly, we propose the hypothesis that this multi-metal dyshomeostasis serves as a critical upstream mechanism driving RIOM repair failure by activating ferroptosis and inducing mitochondrial dysfunction. Consequently, the targeted reconstruction of local metal homeostasis is expected to achieve synergistic tissue repair. Based on the competitive displacement principle of coordination chemistry, this project proposes the design and synthesis of a magnesium/zinc-curcumin complex (MgZn-Cur), which is further integrated with a γ-polyglutamic acid/polylysine network to formulate an in situ hydrogel spray (MgZn-Cur@PP). Exploiting the high stability constant between iron and curcumin, this system competitively displaces Mg and Zn within the iron-overloaded microenvironment. This enables a sophisticated ion-exchange regulation strategy that simultaneously chelates excessive iron and supplements depleted magnesium and zinc. Specifically, this study will: (1) systematically characterize the physicochemical properties and the ion-exchange mechanism of the MgZn-Cur@PP hydrogel; (2) elucidate the underlying mechanisms by which multi-metal dyshomeostasis triggers ferroptosis and mitochondrial damage; and (3) evaluate the in vivo repair efficacy and biosafety of the hydrogel spray using animal models. By interpreting the pathogenesis of RIOM from the unprecedented perspective of multi-metal dyshomeostasis, this study is expected to provide novel insights and a solid theoretical foundation for the clinical treatment of RIOM.