Among different hollow nanostructures, the preparation of hollow mesoporous silica nanoparticles (HMSNs) is still a
hotspot research field due to their unique properties e.g., large pore sizes and volumes, high drug loading capacity,
ease of surface modification, large surface area, and biodegradability. Herein, novel uniform HMSNs are prepared
for the first time by a combination of heterogeneous oil-water biphase stratification and simple mono-, di-, and tri-
valent etching reactions. The biphase stratification reaction allows self-assembly of reactants at the oil−water inter-
face, while the subsequent step is designed for the efficient selective silica etching under mild conditions. We have
studied the effect of cation's valence (NH4+ , Ca2+ , and Al3+ ) on the silica etching reaction coupled with the biphase
stratification reaction both in the absence and presence of the auxiliary pore expanded agent 1, 3, 5 trimethylbenzene
(TMB). In the absence of TMB, the Brunauer–Emmett–Teller (BET) analysis confirms that Al3+ creates materials with
the largest pore size (18.0 nm), whereas the use of NH4+ results in the largest pore volume (2.30 cm3 /g). The pores gen-
erated using Ca2+ and Al3+ as silica etching agents have a volume 2.01 cm3 /g and 2.05 cm3 /g, respectively. Similar
experiments in the presence of TMB leads to the formation of HMSN with larger pore sizes (24 nm and 21.5 nm) and
volumes (2.70 cm3 /g and 2.12 cm3 /g) when using Al3+ and Ca2+ , respectively, as etching agents. Drug loading capac-
ity using Langmuir adsorption model indicate our hollow MSN material exhibit the high adsorbing DOX up to
558.23 mg per gram of nanoparticles in pH of 7.2. Furthermore, synthetized NPs exhibited high loading capacity
for large protein and biomolecules such as BSA. Our findings confirmed that the charge density of cation has a critical
role on selective silica etching in the preparation of HMSNs