Importance of Robust and Reliable Nanochannel Sealing for Enhancing Drug Delivery Efficacy of Hollow Mesoporous Nanocontainer.

Hollow mesoporous silica nanoparticles (HMSNPs) have been widely explored in the biomedical field as drug delivery nanocarriers by virtue of their large hollow cavity. However, the connectivity between the internal cavity and the outside environment by numerous nanochannels on the mesoporous shell allows for possible drug leakage, leading to nonsufficient drug loading due to unreliable capping of the nanopores. In addition, the issue of ensuring effective utilization of the hollow cavity for achieving high drug loading capacity of HMSNPs is seldom addressed. Thus, in this work, HMSNPs with the diameter of about 400 nm were prepared and completely encapsulated by growing an ultrathin nanolayer of aluminum oxide (Al 2 O 3 ) of about 20 nm on the surface of the mesoporous shell with template-assisted sol-gel chemistry. The robust sealing layer of Al 2 O 3 can ensure "zero release" of the delivery system under neutral conditions, which is crucial for achieving high drug loading capacity by physical encapsulation of cargo molecules within the hollow cavity. The Al 2 O 3 -coated HMSNP (denoted as HMSNP Al 2 O 3 can improve the drug loading capacity up to about 35 wt %, realizing loading efficiency as high as ten times the maximum value without Al 2 O 3 under the same conditions. Besides, the encapsulation nanolayer of Al 2 O 3 would be degraded under the acidic condition to realize pH-responsive controlled release of the cargo molecules. We further carried out in vitro drug delivery experiments by using human epithelial cervix adenocarcinoma (HeLa) cells as the model and revealed much higher drug delivery efficacy within cancer cells compared to free doxorubicin (Dox) and Dox loaded HMSNP without sealing (HMSNP@Dox). The current work not only clarifies the importance of the surface encapsulation of the nanochannels when using HMSNPs as nanocarriers, but also provides a strategy to prepare fully encapsulated core-shell structures, which holds great potential for physically encapsulating various theranostic reagents in the biomedical field.