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

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 (Fe3+), 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.