Shutting Down the 'Language Encoder': A Pathogen-Derived Nano-Interferer Disrupt Sialylation Metabolism and Reprogram Intercellular Communication in Glioblastoma

Glioblastoma (GBM), constrained by the limited cranial space and the blood-brain barrier (BBB), establishes a rapidly adaptable, generalized communication network through enhanced terminal sialylation of membrane proteins. This metabolism-driven network encodes cellular metabolic states into functional information at the membrane level, thereby markedly enhancing signaling plasticity, intercellular communication, and immune evasion, which together sustain and expand malignant phenotypes within a resource-limited microenvironment. Here, a "metabolism-guided decoding of communication architecture" strategy is proposed and developed a brain-targeted pathogen-derived nano-interferer (OMV@HM-T/F). By simultaneously inhibiting glycosylation precursor synthesis and sialic acid activation, the platform remodels membrane glycan structures, disrupts glycan-dependent communication scaffolds, and effectively blocks downstream signal amplification and immune suppression pathways. Integrating BBB penetrability with tumor microenvironment responsiveness, this strategy enables precise metabolic-level intervention, offering a promising approach to overcoming high adaptability and therapeutic resistance.

bacterial outer membrane; immune modulation; intercellular communication; membrane proteins; metabolic regulation; nano‐interferer, sialylation.