It is urgent for patients with chronic kidney disease (CKD) to develop a robust and facile therapy for effective control of serum phosphate and reasonable regulation of gut microbiota, which are aiming to prevent cardiovascular calcification and reduce cardiovascular complications. Here, bioinspired by intestinal microstructures, we developed biomimetic wrinkled prebiotic-containing microspheres with enhanced intestinal retention and absorption for reducing hyperphosphatemia and vascular calcification of CKD model rats. The resultant CSM@5 microspheres exhibited favorable phosphate binding capacity in vitro and could effectively reduce serum concentration of phosphorous in vivo. Through increasing the beneficial bacteria and decreasing the harmful bacteria in the intestinal tract, these prebiotic microspheres can modulate intestinal microbiota and then ameliorate vascular calcification notably. This feasible and robust approach may offer a potential and effective strategy for the treatment of hyperphosphatemia of CKD and prevention of its cardiovascular complications.