Core-shell structured covalent-organic frameworks (COFs) have rarely been reported because of the essentially inevitable crystallographic structural distinctions of different COF species. In this contribution, we outline a novel strategy for constructing core-shell structured COFs from interpenetration isomers and take the classic three-dimensional COF-300 as a proof-of-concept. Core-shell particles with 5-fold interpenetrated COF-300 as the core and 7-fold interpenetrated COF-300 as the shell were prepared via a two-step process, using exactly the same monomers but under different reaction conditions within each step. Moreover, the thicknesses of both the core and shell show adjustable characteristics. This approach may promote the future advancement of hierarchical microstructures with predesigned functions in different hierarchies.