Abstract: Flotation drug delivery system (FDDS) is recognized as an efficient mean to improve the therapeutic efficiency and to enhance the drug bioavailability. Herein, we have developed a molecularly imprinted polymer (MIP) against capecitabine (CAP) to fabricate FDDS by exploiting polyhedral oligomeric silsesquioxane (POSS) and mobil composition of matter No. 41 (MCM-41) as the codopant. The synergistic effect of POSS and MCM-41 endows MIPs with enhanced imprinting effect and improved mass transfer efficiency. The impacts of the type of dopant, the type of functional monomer, the template/functional monomer ratio and the functional monomer/cross-linker ratio on imprinting effect have been investigated in detail. The POSS/MCM-41 codoped MIPs present favorable sustained release property in vitro and in vivo, displaying a high relative bioavailability of 173.4%. The proposed MIPs with high selectivity and superior physical and chemical stability exhibit the potential as an alternative drug carrier applied in FDDS