Core-shell hierarchical mesostructured silica nanoparticles for gene/chemo-synergetic stepwise therapy of multidrug-resistant cancer

The design and synthesis of hierarchically nanoporous structures for the co-encapsulation and sequential releases of different cargos are still great challenges in biomedical applications. In this work, we report on the elaborate design and controlled synthesis of a unique core-shell hierarchical mesoporous silica/organosilica nanosystem, in which there are large and small mesopores separately present in the shell and core, facilitating the independent encapsulations of large (siRNA) and small (doxorubicin) molecules, respectively. Importantly, the framework of the organosilica shell is molecularly hybridized with disulfide bonds, which enables the unique responsiveness to the reductive tumor microenvironment for the controlled releasing of loaded gene molecules, followed by the subsequent doxorubicin release. The first released large siRNA molecules from the organosilica shell down-regulated the expression of P-gp in the cell membrane and reversed the MDR of cancer cells, thus enhancing the antitumor effect of subsequently released small DOX molecules from the silica core, and in such a synergetic way the MDR tumor growth can be efficiently inhibited. This work shows the significant advantages compared to the traditional small-mesoporous or large-mesoporous nanosystems for drug co-delivery.