Shutting Down the ‘Language Encoder’: A Pathogen-Derived Nano-Interferer Disrupt Sialylation Metabolism and Reprogram Intercellular Communication in Glioblastoma
Time：2025/12/3 13:25:00 Views：71
Aberrant enhancement of terminal sialylation in glioblastoma (GBM) has been established as a critical metabolic determinant for maintaining membrane receptor homeostasis, constructing high-throughput intercellular communication networks, and ultimately promoting immune evasion and therapy resistance. In this study, we propose a hierarchical, metabolism-guided blockade strategy that systematically intervenes in cell surface sialylation by simultaneously inhibiting glycosylation precursor synthesis and sialic acid activation. Leveraging GBM’s metabolic dependence on sialic acid-containing glycoconjugates, we engineered a pathogen-derived nano-interferer with blood–brain barrier (BBB) permeability, enabling targeted delivery of regulatory molecules and microenvironment-responsive release. By disrupting sialylation-dependent signal integration and intercellular communication networks, this approach significantly reduces signaling plasticity in tumor cells and offers a potential strategy to overcome metabolism-driven therapeutic resistance. The study is reported in Advanced Materials under the title Shutting Down the ‘Language Encoder’: A Pathogen-Derived Nano-Interferer Disrupts Sialylation Metabolism and Reprograms Intercellular Communication in Glioblastoma.
The progression of GBM is constrained by limited cranial space and the structural barrier imposed by the BBB, with tumor survival relying on extensive remodeling of energy metabolism, glycan assembly, and membrane structural functionality. Sialylation, a post-translational modification tightly coupled to energy metabolism, regulates the conformational stability and ligand recognition of multiple membrane receptors, including EGFR and PD-1/PD-L1, thereby expanding the signaling processing capacity of tumor cells under resource-limited conditions. Extensive evidence indicates that key sialyltransferases, such as ST6GAL1, are significantly upregulated in GBM, with enrichment of terminal sialylation on the cell surface strongly correlating with malignancy, immunosuppressive activity, and poor prognosis. Existing desialylation strategies largely rely on exogenous enzymatic treatments, which are limited by delivery efficiency, stability, and the risk of compensatory metabolic activation, restricting their clinical applicability.
Upon identifying GBM’s structural dependence on sialic acid metabolism, we developed a BBB-permeable, tumor microenvironment-responsive nano-interferer (OMV@HM-T/F). By integrating the innate brain-targeting properties of outer membrane vesicles with a biodegradable mesoporous core, this platform enables stable loading and responsive release of metabolic regulatory agents. The system implements a dual-node intervention along the sialylation pathway, simultaneously inhibiting glycan precursor synthesis and CMP-sialic acid activation. This not only remodels cell surface glycan structures but also disrupts the continuity of the glycan–receptor–signal axis, substantially reducing the stability and redundancy of intercellular communication networks and enhancing tumor sensitivity to therapeutic intervention.
Dr. Jingyi Zhou, a doctoral student, is the first author of the paper, Prof. Chen Jiang is the corresponding author, and Associate Prof. Tao Sun is a co-corresponding author. This study was supported by the National Natural Science Foundation of China, the Shanghai Major Science and Technology Projects, the Pingyuan Laboratory, and the Zhangjiang Laboratory.
Original article link: https://advanced.onlinelibrary.wiley.com/doi/full/10.1002/adma.202516608
