A Self-Homing Liposomal Nanobot for Active Therapy of Glioblastoma.

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.