Reversal of Chemoresistance via Staged Liberation of Chemodrug and siRNA in Hierarchical Response to ROS Gradient

P‐glycoprotein (P‐gp)‐mediated multidrug resistance (MDR) often leads to the failure of antitumor chemotherapy, and codelivery of chemodrug with P‐gp siRNA (siP‐gp) represents a promising approach for treating chemoresistant tumors. To maximize the antitumor efficacy, it is desired that the chemodrug be latently released upon completion of siP‐gp‐mediated gene silencing, which however, largely remains an unmet demand. Herein, core–shell nanocomplexes (NCs) are developed to overcome MDR via staged liberation of siP‐gp and chemodrug (doxorubicin, Dox) in hierarchical response to reactive oxygen species (ROS) concentration gradients. The NCs are constructed from mesoporous silica nanoparticles (MSNs) surface‐decorated with cRGD‐modified, PEGylated, ditellurium‐crosslinked polyethylenimine (RPPT), wherein thioketal‐linked dimeric doxorubicin (TK‐Dox 2 ) and photosensitizer are coencapsulated inside MSNs while siP‐gp is embedded in the RPPT polymeric layer. RPPT with ultrahigh ROS‐sensitivity can be efficiently degraded by the low‐concentration ROS inside cancer cells to trigger siP‐gp release. Upon siP‐gp‐mediated gene silencing and MDR reversal, light irradiation is performed to generate high‐concentration, lethal amount of ROS, which cleaves thioketal with low ROS‐sensitivity to liberate the monomeric Dox. Such a latent release profile greatly enhances Dox accumulation in Dox‐resistant cancer cells (MCF‐7/ADR) in vitro and in vivo, which cooperates with the generated ROS to efficiently eradicate MCF‐7/ADR xenograft tumors.