Yi‐Sheng Liu, Li Xi, Qionghua Zhu, Yong Zhong, Xuhong Lin, Chaoqun Zhou, Cai Qi, Jincheng Guo, Qinqin Ma, Haigang Wu, Gaoyang Wang, Feng Bai, Jiefei Wang
Glioblastoma multiforme (GBM) remains a formidable therapeutic challenge due to its high invasiveness, the highly restrictive blood-brain barrier (BBB), and frequent drug resistance, necessitating new therapeutic strategies. Here, we developed tellurium-selenium nanoparticles (TeSe NPs) with exceptional near-infrared (NIR) chiroptical properties and potent antitumor activity against drug-resistant glioma for the first time. Notably, the right-handed nanoparticles (D-TeSe NPs) exhibited higher cellular uptake than left-handed L-TeSe NPs through chirality-selective recognition by drug-resistant glioma cells. The Te and Se active centers in D-TeSe NPs selectively triggered severe oxidative stress in glioma cells, leading to redox imbalance, reactive oxygen species (ROS)-mediated mitochondrial dysfunction, and ultimately causing 44.2% glioma cell death (versus 37.1% for L-TeSe NPs). When combined with 808 nm right-handed circularly polarized light, D-TeSe NPs showed enhanced ROS generation, elevating therapeutic efficacy to 62.5% while maintaining negligible toxicity to normal cells. Furthermore, apolipoprotein E-functionalized D-TeSe NPs demonstrated improved BBB penetration and tumor-targeting capability, significantly extending the survival of mice with orthotopic drug-resistant glioma to 52 days (versus 21 days for PBS control). This study pioneers a NIR and brain-targeted chiral nanoplatform for precision therapy of orthotopic glioma, offering a chirality-driven paradigm against drug-resistant malignancies and other brain diseases.