The spatial distribution of MOF functionalization reveals that postsynthetic modification (PSM)-derived microstructures can range from uniform to core-shell, affected by reagent reactivity and solvent choice. A suite of isocyanate reagents with varying reactivity were employed to study the effect of kinetics and experimental conditions on microstructure during PSM. Exploiting the difference in reactivity between chloroacetyl isocyanate and 4-bromophenyl isocyanate, a one-pot PSM reaction produces a dual-functionalized core-shell structure. Furthermore, a triple-functionalized Matryoshka structure is formed in a two-step PSM procedure using trifluoroacetyl isocyanate followed by a self-sorting reaction with chloroacetyl isocyanate and 4-bromophenyl isocyanate, demonstrating that a better understanding of the dynamics of PSM can support the design of MOFs with increasingly sophisticated architectures.