Here we demonstrate a general approach to crafting a myriad of soluble octa-functionalized POSS derivatives by manipulating the sequential click reactions. After flexible modification with bio-functional groups, these uniform POSSs possess good biocompatibility, remarkable anticancer therapeutic effect and outstanding antibacterial activity in aqueous solutions. Notably, this 'one-pot' approach provides a simple strategy to produce customized POSS macromolecules, which may afford a novel platform for clear elucidation of more complex mechanisms and precise fabrication of high-performance biomaterials in various applications.