Carboxymethyl chitosan-based injectable hydrogel immobilizing single-atom nanozymes for localized ROS amplification and ferroptosis-enhanced postoperative oral cancer therapy.

Postoperative recurrence of oral squamous cell carcinoma (OSCC) remains a major clinical challenge, necessitating the development of localized and sustained-release therapeutic platforms. Herein, we report an injectable hydrogel nanocomposite system based on carboxymethyl chitosan (CMCS) and 4-arm polyethylene glycol-benzaldehyde (4-arm-PEG-CHO), crosslinked via dynamic Schiff base bonds, for site-specific and prolonged therapeutic delivery. This carbohydrate polymer-based hydrogel encapsulates polyethylenimine-modified iron single-atom nanozymes (FeSAzymes), glucose oxidase (GOx), and liposome-encapsulated buthionine sulfoximine (LipBSO) to achieve synergistic chemodynamic therapy (CDT) and ferroptosis. GOx catalyzes endogenous glucose into hydrogen peroxide (H₂O₂), which is converted by FeSAzymes into cytotoxic hydroxyl radicals (·OH), amplifying oxidative stress. Simultaneously, LipBSO inhibits glutathione biosynthesis, depletes intracellular antioxidants, and downregulates GPX4 to induce ferroptosis. The CMCS-based hydrogel matrix ensures sustained release, tumor retention, and enhanced therapeutic efficacy with minimal systemic toxicity. In vitro and in vivo evaluations demonstrated significant suppression of OSCC recurrence through dual-mode ROS-mediated cytotoxicity. This study highlights the potential of carbohydrate polymer-based injectable hydrogels as multifunctional delivery vehicles for localized and combinatorial cancer therapy.