Abstract

The ingenious construction of transition metal-containing nanomaterials holds great potential for desired chemodynamic therapy (CDT). Herein, Cu 2+ -based porous metal–organic frameworks (MOFs) were laterally grown on the substrate of ultrathin sSiO 2 nanosheets (NSs) for high-efficiency chloroquine (CQ) loading, which was then modified by CD44-targeted hyaluronic acid (HA) to develop targeted sandwich-like two-dimensional (2D) NSs (HA-CQ/ [email protected] 2 NSs) for activatable autophagy inhibition-primed CDT. Specifically, the obtained HA-CQ/ [email protected] 2 NSs initiated the reduction of Cu 2+ to Cu + by depleting overexpressed glutathione (GSH), which concomitantly induced the decomposition of MOFs for controllable cargo unloading. The formed Cu + then exerted Fenton-like catalyzing activity to generate detrimental hydroxyl radicals ( OH) for ROS-involved CDT. Meanwhile, the released CQ was utilized to inhibit autophagy via blocking autolysosomes formation and degradation, thereby turning off self-protection pathway of oxidative stress for harvesting autophagy inhibition-primed chemodynamic activity. Particularly, HA-CQ/ [email protected] 2 NSs could effectively accumulate at tumor site and be rapidly internalized into tumor cells benefiting from unique sheet-like morphology and CD44-targeting specificity. Both in vitro and in vivo results confirmed the potent autophagy inhibition-primed CDT effect, suggesting the activatable targeted sandwich-like 2D NSs may be referential to the creative design of therapy regimen.