Multimetallic architectures that combine chemically diverse materials to affect tandem reactions within a single scaffold drive future nanocatalyst development.Here, we show the unique, interlattice growth of the small molecule activating Ag 0 guest within the Lewis acidic/basic Fe 3 O 4 octahedral host (Fe 3 O 4 @Ag-40, 10, 6, 2 at %) via a polyol-hydrothermal procedure. Microscopic (scanning electron microscopy and energy-dispersive X-ray spectroscopy ) and structural characterization (powder X-ray diffraction and X-ray photoelectron spectroscopy) of the Fe 3 O 4 @Ag hybrid materials reveal doping of Ag 0 in O h Fe 2+ substitutional vacancies of the Fe 3 O 4 host and Ag 0 nanoparticle growth on and embedded deep within (>400 nm, Ar + sputtering) the octahedra. These hybrid materials activate CO 2 and perform C(sp)−H and C(sp 3 )−Cl bond scission of alkyne substrates to selectively produce lactone heterocycles in up to 85% yield. Control reactions delineate two distinct pathways for the mechanism involving the complementarity of interfacial sites where alkyne activation occurs at Fe−O sites and CO 2 incorporation is predominately managed by Ag 0 . The recyclability of the Fe 3 O 4 @Ag-40B hybrid catalyst is demonstrated over five cycles and it shows the structural integrity of the octahedra, but a gradual drop in yield of the product from 85 to 45% due to slow depletion of surface Ag NPs is observed. Together, these results illustrate a rare understanding of the cooperative synergy and mechanism of multimetallic nanocatalyst interfaces for multiple substrate reactivity.