Reversal of Chemo-Resistance 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 anti-tumor chemotherapy, and co-delivery of chemodrug with P-gp siRNA (siP-gp) represents a promising approach for treating chemo-resistant tumors. To maximize the anti-tumor 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) were 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 were 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 were co-encapsulated inside MSNs while siP-gp was embedded in the RPPT polymeric layer. RPPT with ultra-high 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 was performed to generate high-concentration, lethal amount of ROS, which cleaved thioketal with low ROS-sensitivity to liberate the monomeric Dox. Such a latent release profile greatly enhanced Dox accumulation in MCF-7/ADR cells, which cooperated with the generated ROS to efficiently eradicate MCF-7/ADR xenograft tumors in vitro and in vivo. This article is protected by copyright. All rights reserved.