Activatable autophagy inhibition-primed chemodynamic therapy via targeted sandwich-like two-dimensional nanosheets.

• MOF-containing sandwich-like 2D nanosheets were constructed via a mild method. • The targeted nanosheets showed the activatable drug release and OH generation. • The nanosheets possessed an effective cellular uptake and tumor enrichment. • The autophagy inhibition could promote the ROS-involved chemodynamic activity. The ingenious construction of transition metal-containing nanomaterials holds great potential for desired chemodynamic therapy (CDT). Herein, Cu2+-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/HT@sSiO 2 NSs) for activatable autophagy inhibition-primed CDT. Specifically, the obtained HA-CQ/HT@sSiO 2 NSs initiated the reduction of Cu2+ 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/HT@sSiO 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. [ABSTRACT FROM AUTHOR]