Abstract

Giant heterometallic polyoxometalate (POM) clusters with precise atom structures, flexibly adjustable and abundant active sites are promising for constructing functional nanodrugs. However, current POM drugs are almost vacant in orthotopic brain tumor therapy due to the inability to effectively penetrate the blood–brain barrier (BBB) and low drug activity. Here, we designed the largest (3.0 nm × 6.0 nm) transition-metal–lanthanide co-encapsulated POM cluster {[Ce₁₀Ag₆(DMEA)-(H₂O)₂₇W₂₂O₇₀][B-α-TeW₉O₃₃]₉}₂ ^88- featuring 238 metal centers via synergistic coordination between two geome-try-unrestricted Ce³⁺ and Ag⁺ linkers with tungsten-oxo cluster fragments. This POM was combined with brain-targeted peptide to prepare a brain-targeted nanodrug that could efficiently traverse BBB and target glioma cells. The Ag⁺active centers in the nanodrug specifically activate reactive oxygen species to regulate the apoptosis pathway of glioma cells with a low half-maximal inhibitory concentration (5.66 μM). As the first brain-targeted POM drug, it efficiently prolongs the survival of orthotopic glioma-bearing mice.