Hydrogel-encapsulated nanoenzymes with pH-responsive multienzyme activity for residual tumor clearance

Brain gliomas, marked by their invasive nature, proximity to vital brain areas, and diffuse growth patterns, make their complete surgical resection quite challenging. To address this, we developed a hydrogel nanocomposite (MCAG-Gel) tailored for postoperative glioma treatment, which is constructed by gel loading manganese-doped hollow cerium oxide nanoparticles (MnO_x/CeO_x, MC NPs) and the chemotherapeutic drug axitinib (AG). MCAG-Gel adheres to the post-surgery wound and is responsive to the weakly acidic tumor microenvironment (TME), releasing MC NPs and AG for chemotherapy. Interestingly, MC NPs exhibit peroxidase-like (POD) activity and catalase-like (CAT) activity in the TME, generating reactive oxygen species (ROS) to inhibit residual glioma cells while depleting glutathione to amplify oxidative stress and alleviate tumor hypoxia. Conversely, under physiological conditions, MC NPs exhibit CAT-like and superoxide dismutase (SOD)-like activities, scavenging ROS to protect normal tissues from oxidative damage. MCAG-Gel shows good biosafety and potent anti-tumor efficacy against postoperative residual tumors in a subcutaneously implanted glioblastoma model. Collectively, these findings highlight the potential of MCAG-Gel as a promising therapeutic strategy for clinical postoperative glioma treatment.