In the present study, three water-soluble drugs (propranolol hydrochloride, PNH; diltiazem hydrochloride, DZH; levofloxacin hydrochloride, LFH) with different number of hydrogen bonding acceptors were used as guest drug molecules, and three kinds of biomimetic synthesized nanoporous silica@poly(ethyleneimine)s xerogel (NS@P xerogel, 25%NS@P xerogel and 75%NS@P xerogel) were taken as host drug carriers. Mutural interaction formed between guest drug molecules and host drug carriers were investigated using a two-level three-factorial central composite design. The results confirmed that water-soluble drug loaded three nanoporous silica carriers presented the same regular controlled release effect, which was 75%NS@P xerogel > 25%NS@P xerogel > NS@P xerogel. The main contribution to burst release was the pore diameter of host carrier. Accomplishment of cumulative release in 24 h can be obtained when loading guest drug molecules with small number of hydrogen bonding acceptors to host carriers with either quite small or large pore diameter. The present work can favor to explore the mutural interaction between host carrier and guest drug molecules and thus promoted the development of nanoporous silica in pharmaceutical application.