A formaldehyde-assisted metal–ligand crosslinking strategy is used for the synthesis of metal–phenolic coordination spheres based on sol–gel chemistry. A range of mono-metal (Co, Fe, Al, Ni, Cu, Zn, Ce), bi-metal (Fe-Co, Co-Zn) and multi-metal (Fe-Co-Ni-Cu-Zn) species can be incorporated into the frameworks of the colloidal spheres. The formation of coordination spheres involves the pre-crosslinking of plant polyphenol (such as tannic acid) by formaldehyde in alkaline ethanol/water solvents, followed by the aggregation assembly of polyphenol oligomers via metal–ligand crosslinking. The coordination spheres can be used as sensors for the analysis of nucleic acid variants with single-nucleotide discrimination, and a versatile precursor for electrode materials with high electrocatalytic performance.