Nanomaterials functionalized with metal oxide species have aroused broad research interest in biomedical, catalysis and adsorption applications. However, a generalized functionalization approach achieving both high dispersity and high content of metal oxide species is rarely reported. In this study, a novel three-dimensional nanosponge (3D-NS) enabled strategy is developed to tackle this challenge. Instead of directly modifying metal species onto nanoparticles as performed in conventional approaches, the “empty” pores of nanoparticles are creatively converted into a “sponge-like” 3D nanospace by filling up with resoles rich in metal anchors, which efficiently accommodate high content metal species and maintain their highly dispersed state during the fabrication process. This strategy is generic to achieve highly dispersed metal functionalization of different single and binary metal compositions. As a demonstration, highly dispersed copper species derived from this strategy show excellent Fenton-like catalytic activity and enhanced cancer cell inhibition performance. These findings provide new understanding and useful tools for the development of metal functionalized nanomaterials for advanced applications.