胶质母细胞瘤 (GBM) 由于其侵袭性和药物对血脑屏障 (BBB) 的渗透有限而带来了重大的治疗挑战。为此，我们在这里提出了一种创新的仿生方法，涉及开发基因工程外泌体纳米催化剂（Mn@Bi2Se3@RGE-Exos），通过改善血脑屏障渗透和类酶催化活性来实现有效的 GBM 治疗。有趣的是，在这样的纳米系统中观察到光热激活的多重酶样反应性。在 NIR-II 光照射下，Mn@Bi2Se3@RGE-Exos 能够将过氧化氢转化为羟基自由基、氧和超氧自由基，提供类似过氧化物酶 (POD)、氧化酶 (OXD) 和过氧化氢酶 (CAT) 的纳米催化作用级联。因此，这会导致强烈的氧化应激，从而损害 GBM 细胞。体外、体内和蛋白质组学分析进一步揭示了 Mn@Bi2Se3@RGE-Exos 破坏细胞稳态、增强免疫反应和诱导癌细胞铁死亡的潜力，展示了抗 GBM 的巨大前景具有良好的生物安全性。总的来说，这项研究的成功为刺激响应纳米催化医学的未来设计和临床研究提供了可行的策略，特别是在像 GBM 这样具有挑战性的脑癌的背景下。

Glioblastoma (GBM) poses a significant therapeutic challenge due to its invasive nature and limited drug penetration through the blood-brain barrier (BBB). In response, here we present an innovative biomimetic approach involving the development of genetically engineered exosome nanocatalysts (Mn@Bi2Se3@RGE-Exos) for efficient GBM therapy via improving the BBB penetration and enzyme-like catalytic activities. Interestingly, a photothermally activatable multiple enzyme-like reactivity is observed in such a nanosystem. Upon NIR-II light irradiation, Mn@Bi2Se3@RGE-Exos are capable of converting hydrogen peroxide into hydroxyl radicals, oxygen, and superoxide radicals, providing a peroxidase (POD), oxidase (OXD), and catalase (CAT)-like nanocatalytic cascade. This consequently leads to strong oxidative stresses to damage GBM cells. In vitro, in vivo, and proteomic analysis further reveal the potential of Mn@Bi2Se3@RGE-Exos for the disruption of cellular homeostasis, enhancement of immunological response, and the induction of cancer cell ferroptosis, showcasing a great promise in anticancer efficacy against GBM with a favorable biosafety profile. Overall, the success of this study provides a feasible strategy for future design and clinical study of stimuli-responsive nanocatalytic medicine, especially in the context of challenging brain cancers like GBM.