Multifunctional Nanoplatform for Mild Microwave-Enhanced Thermal, Antioxidative, and Chemotherapeutic Treatment of Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is usually associated with excessive proliferation of M1-type proinflammatory macrophages, resulting in severe hypoxia and excess reactive oxygen species (ROS) in the joint cavity. Inhibiting M1-type proinflammatory macrophages and/or repolarizing them into M2 phenotype anti-inflammatory cells by alleviating hypoxia and scavenging ROS could be a promising strategy for RA treatment. In this work, a microwave-sensitive metal-organic framework of UiO-66-NH2 is constructed for coating a nanoenzyme of cerium oxide (CeO2) and loading with the drug celastrol (Cel) to give UiO-66-NH2/CeO2/Cel, which is ultimately wrapped with hyaluronic acid (HA) to form a nanocomposite UiO-66-NH2/CeO2/Cel@HA (UCCH). With the microwave-susceptible properties of UiO-66-NH2, the thermal effect of microwaves can eliminate the excessive proliferation of inflammatory cells. In addition, superoxide-like and catalase-like activities originating from CeO2 in UCCH are boosted to scavenge ROS and accelerate the decomposition of H2O2 to produce O2 under microwave irradiation. The nonthermal effect of microwaves could synergistically promote the repolarization of M1-type macrophages into the M2 phenotype. Accompanied by the release of the anti-RA chemotherapeutic drug Cel, UCCH can efficiently ameliorate RA in vitro and in vivo through microwave-enhanced multisynergistic effects. This strategy could inspire the design of other multisynergistic platforms enhanced by microwaves to exploit new treatment modalities in RA therapies.

Prodrug-Based Nanoreactors with Tumor-Specific In Situ Activation for Multisynergistic Cancer Therapy.

Efficient drug delivery into tumor cells while bypassing many biological barriers is still a challenge for cancer therapy. By taking advantage of the palladium (Pd)-mediated in situ activation of a prodrug and the glucose oxidase (GOD)-based ß-d-glucose oxidation reaction, we developed a multisynergistic cancer therapeutic platform that combined doxorubicin (DOX)-induced chemotherapy with GOD-mediated cancer-orchestrated oxidation therapy and cancer starvation therapy. In the present work, we first synthesized DOX prodrugs (pDOXs) and temporarily assembled them with ß-cyclodextrins to reduce their toxic side effects. Then, a nanoreactor was constructed by synthesizing Pd0 nanoparticles in situ within the pores of mesoporous silica nanoparticles for the conversion of pDOX into the active anticancer drug. Furthermore, GOD was introduced to decrease the pH of the tumor microenvironment and induce cancer-orchestrated oxidation/starvation therapy by catalyzing ß-d-glucose oxidation to form hydrogen peroxide (H2O2) and gluconic acid. Our study provides a new strategy that employs a cascade chemical reaction to achieve combined orchestrated oxidation/starvation/chemotherapy for the synergistic killing of cancer cells and the suppression of tumor growth.