A Self‐Homing Liposomal Nanobot for Active Therapy of Glioblastoma

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Abstract Glioblastoma (GBM) remains a substantial obstacle in therapy since the blood–brain barrier (BBB) and tumor microenvironment (TME) severely prevent the access of most exogenous therapeutic agents to the central nervous system. Overcoming this dual defense established by BBB‐TME is a critical challenge in GBM therapy. Here, we present a glucose oxidase (GOD)‐powered liposomal nanobot (lipoNbot) to breach the BBB‐TME through self‐homing navigation guided by the acid and glucose in TME—a mechanism rooted in the regulation of GOD activity, with optimal performance in acidic environments to actively deliver drugs for GBM chemotherapy. The lipoNbot features an asymmetric structure composed of GOD‐modified cancer cell membranes and γ‐glutamylated lipids, which synergistically enhance BBB‐TME penetration through chemotactic diffusiophoresis and γ‐glutamyl transferase (GGT)‐mediated transcytosis. The proton sponge effect facilitates lysosomal escape for BBB traversal. In vivo investigation indicates that lipoNbots achieve a 4.3‐fold increase in delivery efficiency. Such a lipoNbot poses the specific biochemical cues of GBM for self‐homing navigation, establishing a proof‐of‐concept framework utilizing the pathological features for active therapy of central nervous system diseases.

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