Brain‐Targeted Near‐Infrared Chiral TeSe Nanodrug Against Orthotopic Drug‐Resistant Glioma

Abstract 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.