Allosteric DNA Nanorobots for Targeted Glioma Therapy: Acid‐Triggered Doxorubicin Delivery

ABSTRACT Chemotherapy remains the primary therapeutic option for glioma treatment due to its noninvasive nature and broad applicability. However, most existing chemotherapeutic carriers suffer from poor blood‐brain barrier (BBB) permeability and undefined drug delivery mechanisms, limiting their effectiveness in brain tumor therapy. Here, we present an allosteric DNA nanorobot for targeted glioma therapy, engineered via DNA origami for acid‐triggered doxorubicin (Dox) delivery. This nanorobot features cytosine‐rich pH sensors that facilitate its assembly into a stable tetrahedral configuration, crucial for efficient BBB traversal. Striking in vitro and in vivo studies demonstrate that these Dox‐loaded nanorobots not only effectively cross the BBB but also accumulate in glioma tissues, resulting in significant suppression of tumor growth. We decode the drug delivery mechanism: acid‐induced destabilization of DNA nanorobots triggers Dox release with optimal bioavailability. This pioneering nanorobot, powered by pH‐responsive allosteric dynamics, enables revolutionary precision glioma therapy.