Engineering 2D Cu-composed metal-organic framework nanosheets for augmented nanocatalytic tumor therapy.

The engineered nanoformulation that can be activated by intracellular tumor microenvironment, including acidic pH, overexpressed H2O2, and high concentration of glutathione (GSH), features high efficacy to eradicate tumor cells with the intrinsic specificity and therapeutic biosafety. However, the relatively slow reaction rate of traditional Fe2+-mediated Fenton reaction induces the low production amount of reactive oxygen species (ROS) and subsequently the limited therapeutic outcome against tumors. Here, we established Cu (II)-based two-dimensional (2D) metal-organic framework (MOF) nanosheets as a distinct chemoreactive nanocatalyst for GSH-triggered and H2O2-augmented chemodynamic therapy (CDT), depending on the "AND" logic gate, for significant tumor suppression. After internalization by tumor cells, the MOF catalytic nanosheets reacted with local GSH for inducing GSH consumption and reducing the Cu2+ into Cu+. Subsequently, abundant hydroxyl radicals (·OH) generation was achieved via Cu+-mediated Fenton-like catalytic reaction. The dual effects of ·OH production and GSH depletion thus enhanced ROS production and accumulation in tumor cells, leading to significant cellular apoptosis and tumor inhibition, which was systematically demonstrated in both 4T1 and MDA-MB-231 tumor models. Therefore, GSH and H2O2, serve as an "AND" logic gate to trigger the Cu+-mediated Fenton-like reaction and reduce GSH level for augmented CDT with high therapeutic specificity and efficacy, thus inducing cellular apoptosis primarily through ferroptosis at the RNA sequence level.

Oxygen-Independent Photocleavage of Radical Nanogenerator for Near-IR-Gated and H2 O-Mediated Free-Radical Nanotherapy.

The oxygen-dependent nature and limited penetration capacity of visible light render the low efficiency of photodynamic therapy in hypoxic and deep-seated tumors. Therefore, the development of oxygen-free photoactivated chemotherapy (PACT) to generate cytotoxic reactive oxygen species by near-IR (NIR) light-cleavable photocages is in high demand. Here, an oxygen-irrelevant PACT strategy based on NIR light-triggered hydroxyl radicals (•OH) generation is developed for free-radical nanotherapy. Blebbistatin-loaded upconversion of mesoporous silica nanoparticles (UCSNs-B) is established to facilitate the high loading efficiency of blebbistatin and implement the efficient transformation of NIR light into blue light for unprecedented direct photorelease of oxygen-independent •OH. Under NIR laser irradiation, UCSNs-B converted NIR light into blue light, thus enabling the photocleavage of blebbistatin to induce the burst of •OH. The •OH burst under NIR laser irradiation further induces cancer cell apoptosis and significant suppression of hypoxic tumors. In addition, the gadolinium ion (Gd3+ )-doped UCSNs-B are used as contrast agents in magnetic resonance imaging to facilitate real-time monitoring of the therapeutic processes. This study effectively demonstrates that the UCSNs-B act as NIR light-triggered photocages to facilitate oxygen-irrelevant •OH bursts, thus providing insights into the development of efficient PACT nanoagents for cancer treatment.