Tumor-Microenvironment-Responsive Mesoporous Manganese Oxide for Photo-Chemotherapy of Glioma

Photochemotherapy has shown great potential for glioma treatment due to its synergistic effects and lower systemic toxicity. However, challenges like the hypoxic tumor microenvironment, insufficient tumor-specific accumulation, and inadequate cellular internalization efficiency still limit its clinical effectiveness. To tackle these issues, we developed a virus-like hollow mesoporous manganese oxide (vHMMn) nanocage coloaded with Temozolomide (TMZ) and indocyanine green (ICG), and surface-functionalized with DSPE-PEG-rabies virus glycopeptide-29 (DSPE-PEG-RVG29). This design aims to boost cellular uptake and alleviate tumor hypoxia for more effective photochemotherapy. After accumulating in tumor tissues via the enhanced permeability and retention (EPR) effect, the nanocage (TMZ/ICG-loaded vHMMn with DSPE-PEG-RVG29, denoted as TI@vHMMnR) could be efficiently and quickly taken up by tumor cells through virus-like surface-assisted cellular adhesion and nicotinic acetylcholine receptor (nAchR)-mediated endocytosis. When exposed to laser irradiation, the nanocage could produce a large amount of reactive oxygen species (ROS), causing mitochondrial dysfunction. At the same time, the vHMMn nanocage could catalyze endogenous H 2 O 2 into oxygen to increase intratumoral oxygen levels, reversing hypoxia and enhancing phototherapeutic efficacy. Moreover, the nanocage could be degraded by the high levels of glutathione (GSH) inside tumor cells, releasing TMZ to cause DNA damage. Our nanocage integrates tumor targeting, hypoxia relief, and photochemotherapy, offering a promising approach for glioma treatment.