The nanoscale chemical spaces inherent in various organic and metal-organic cages or porous solids and liquids have been continuously explored for their nanoconfinement effect on selective adsorption and reaction of small gas or organic molecules. Herein, we aim to rationalize the unconventional chemical reactivities motivated by the cage-confined nanospaces in aqueous solutions, where the robust yet permeable nanospaces defined by the open-cages facilitate dynamic guest exchange and unusual chemical reactions. The high positive charges on [(Pd/Pt)6(RuL3)8]28+ nanocages drive imidazole-proton equilibrium to display a significantly perturbed pKa shift, creating cage-defined nanospaces in solution with distinct intrinsic basicity and extrinsic acidity. The supramolecular cage effect plays pivotal roles in elaborating robust solution nanospaces, controlling ingress-and-egress molecular processes through open-cage portals, and endowing nanocages with transition-state stabilization, amphoteric reactivities and the phase transfer of insoluble molecules, thus promoting chemical transformations in unconventional ways. Consequently, a wide application of cage-confined catalysis with anomalous reactivities may be expected based on this kind of open-cage solution medium, which combines cage nanocavity, solution heterogeneity and liquid-phase fluidity to benefit various potential mass transfer and molecular process options.