Metal‐Supramolecular Drug Delivery System Empowered Meningeal Lymphatic Vessels‐Bridged Intracranial‐Peripheral Dual Immune Modulation for Reversing Glioblastoma Immune Suppression

ABSTRACT Glioblastoma (GBM) presents significant challenges in treatment due to the presence of the blood‐brain barrier (BBB) and immunosuppressive tumor microenvironment (TME). Here, we developed a novel metal‐supramolecular delivery system (FLM@VC) that empowers meningeal lymphatic vessels (MLVs)‐bridged intracranial‐peripheral dual immune modulation to reverse GBM immune suppression. Using coordination‐driven self‐assembly of lipoic acid (LA), iron ions (Fe ³⁺ ), and bovine albumin (BSA), we engineered nanoassemblies with Verubecestat (MK‐8931) encapsulated and with vascular endothelial growth factor C (VEGF‐C) and c(RGDfK) conjugated. Subcutaneously delivered FLM@VC hijacks the MLVs for brain delivery bypassing the BBB, overcoming the limitations of conventional intravenous administration. Upon tumor accumulation, GSH‐responsive disassembly releases MK‐8931 to reprogram TAMs from the pro‐tumoral M2 to the anti‐tumoral M1 phenotype, thereby eliciting proinflammatory cytokine secretion and enhancing phagocytic clearance of GBM cells. Concurrently, VEGF‐C‐mediated MLV expansion enhances dendritic cell (DC) trafficking to deep cervical lymph nodes (dCLNs), potently priming CD8 ⁺ T cell responses. This MLVs‐bridged intracranial‐peripheral dual immunomodulation strategy effectively transforms immunologically “cold” GBM into “hot” tumors, resulting in potent tumor eradication and significantly prolonged survival in orthotopic GBM models. It not only presents a novel paradigm for synergistic GBM immunotherapy but also provides an alternative brain drug delivery approach.