The 30 cationic {(Mo2O4)-O-V(acetate)}(+) units linking 12 negatively charged pentagonal "ligands," {(Mo-VI)-(Mo5O21)-O-VI(H2O)(6)}(6-) of the porous metal-oxide capsule, [{(Mo6O21)-O-VI(H2O)(6)}(12){(Mo2O4)-O-V(acetate)}(30)](42-) provide active sites for catalytic transformations of organic "guests". This is demonstrated using a well-behaved model reaction, the fully reversible cleavage and formation of methyl tert-butyl ether (MTBE) under mild conditions in water. Five independent lines of evidence demonstrate that reactions of the MTBE guests occur in the ca. 6 x 10(3) angstrom(3) interior of the spherical capsule. The Mo atoms of the {(Mo2O4)-O-V(acetate)}(+) linkers-spanning an ca. 3-nm truncated icosahedron-are sterically accessible to substrate, and controlled removal of their internally bound acetate ligands generates catalytically active {(Mo2O4)-O-V(H2O)(2)}(2+) units with labile water ligands, and Lewis- and Bronsted-acid properties. The activity of these units is demonstrating by kinetic data that reveal a first-order dependence of MTBE cleavage rates on the number of acetate-free {(Mo2O4)-O-V(H2O)(2)}(2+) linkers. DFT calculations point to a pathway involving both Mo(V) centers, and the intermediacy of isobutene in both forward and reverse reactions. A plausible catalytic cycle satisfying microscopic reversibility is supported by activation parameters for MTBE cleavage, deuterium and oxygen-18 labeling studies, and by reactions of deliberately added isobutene and of a water-soluble isobutene analog. More generally, pore-restricted encapsulation, ligand-regulated access to multiple structurally integral metal-centers, and options for modifying the microenvironment within this new type of nanoreactor, suggest numerous additional transformations of organic substrates by this and related molybdenum-oxide based capsules.