Ti3C2Tx MXene nanosheet-based drug delivery/cascaded enzyme system for combination cancer therapy and anti-inflammation

Photothermal therapy (PTT)-based combination therapy is an effective approach to cancer treatment. However, there is a possibility of tumor development due to the inflammation caused by PTT. In addition, hyperthermia can cause damage to normal tissues. This work reported a drug delivery/cascade enzyme system based on Ti3C2Tx MXene nanosheets. Ultra-small, degradable mesoporous silica nanoparticles (DS-MSN) were prepared to load phloretin (Phl), which has anti-inflammatory, antioxidant, and anticancer properties. Subsequently, glucose oxidase (GOx) was adsorbed on the surface of DS-MSN. The nanoparticles were then modified on Ti3C2Tx MXene nanosheets and finally treated with polyethylene glycol (PEG) to obtain the multifunctional system named Ti3C2Tx-Phl@DS-MSN-GOx-PEG (TPDMGP). The high near-infrared photothermal conversion efficiency of Ti3C2Tx made it suitable for PTT. GOx and Ti3C2Tx formed a cascade enzyme system inside cancer cells: Ti3C2Tx exhibited catalase (CAT)-like activity that decomposed intracellular hydrogen peroxide (H2O2) into O2, which was provided to GOx for enhanced starvation therapy. GOx in the presence of O2 produces H2O2, for the oxygen production of Ti3C2Tx. Meanwhile, DS-MSN could be degraded in the reducing environment inside cancer cells as it contains disulfide bonds in its backbone, thus releasing Phl for chemotherapy. Such a combination therapy strategy could achieve a satisfactory therapeutic outcome by low-temperature PTT while evading normal tissue damage by high temperature. The anti-inflammatory effects of both Ti3C2Tx and Phl enabled TPDMGP to eliminate the inflammation caused by PTT via the scavenging of reactive oxygen species (ROS). The multifunctional system is expected to generate new paradigms for cancer PTT.