Modulating Nanozyme‐Based Nanomachines via Microenvironmental Feedback for Differential Photothermal Therapy of Orthotopic Gliomas

Abstract Gliomas are common and refractory primary tumors closely associated with the fine structures of the brain. Photothermal therapy (PTT) has recently shown promise as an effective treatment for gliomas. However, nonspecific accumulation of photothermal agents may affect adjacent normal brain structures, and the inflammatory response induced during PTT may result in an increased risk of brain tumor recurrence or metastasis. Here, the design and fabrication of an intelligent nanomachine is reported based on Gd₂O₃@Ir/TMB‐RVG29 (G@IT‐R) hybrid nanomaterials. These nanomaterials enable tumor‐specific PTT and eliminate inflammation to protect normal brain tissue. The mechanism involves the rabies virus glycopeptide‐29 peptide (RVG29) passing through the blood–brain barrier (BBB) and targeting gliomas. In the tumor microenvironment, Ir nanozymes can act as logic control systems to trigger chromogenic reaction amplification of 3,3′,5,5′‐tetramethylbenzidine (TMB) for tumor‐specific PTT, whereas in normal brain tissues, they scavenge reactive oxygen species (ROS) generated by poor therapy and function as protective agents. Autophagy inhibition of Gd₂O₃ enables excellent photothermal therapeutic effects on orthotopic gliomas and protection against inflammation in normal cells. The results of this study may prove useful in developing highly efficient nanomedicines for glioma treatment.