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

Abstract

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.

Manganese‐Based Immunomodulatory Nanocomposite with Catalase‐Like Activity and Microwave‐Enhanced ROS Elimination Ability for Efficient Rheumatoid Arthritis Therapy

“…Synthesis of UiO-66-NH 2 and UiO-66-NH 2 @HA (UH): UiO-66-NH 2 was synthesized according to a previous method performed by the authors. [42] Specifically, anhydrous ZrCl 4 (42 mg, 0.18 mm) and NH 2 -BDC (33 mg, 0.18 mm) were dissolved in 3.5 mL DMF, and 0.1 mL deionized water was added. Then, 1.7 mL glacial acetic acid was added to the solution and the mixture was sonicated for 30 min.…”

“…[48][49][50] It has been reported by us and others that UiO-66-NH 2 with a porous structure is one of the excellent microwave sensitizers, and 0.9% NaCl (saline) in UiO-66-NH 2 enhances the sensitivity of microwaves. [42,51] As shown in Figure S8, Supporting Information, UiO-66-NH 2 with different concentrations (5, 10, and 15 mg mL −1 ), water, and saline were exposed to microwave irradiation (3 W, 450 MHz) for 5 min. The results showed that the temperature of 15 mg mL −1 UiO-66-NH 2 increased to 48.3 °C, while that of water and saline only reached 29.9 and 37.3 °C.…”

“…Macrophages play a key role in immune response, protecting organisms against infection and regulating the development of tissue inflammation. [42] Macrophages are divided into two phenotypes, namely the M1 and M2 macrophages. M1 macrophages participate in the pro-inflammatory process and secrete various markers (iNOS, IL-1𝛽, and TNF-𝛼) to aggravate the development of inflammation and surrounding tissue damage.…”

“…[41] UiO-66-NH 2 can enhance microwave sensitization and plays the role of microwave hyperthermia in the treatment of inflammation as reported recently by us. [42] As shown in Scheme 1, when UMnEH diffuses to the inflammatory site of RA synovium, HA as a naturally occurring component of normal synovial fluid, can gradually lubricate the joints. [43] Meanwhile, Mn-EGCG can be slowly dissociated from the UiO-66-NH 2 upon microwave (MW) irradiation at low pH, and exert its antioxygenic/ROS scavenging activity.…”

Ce1−xZrxO2 nanoparticles in bacterial cellulose, bio-based composites with self-regenerating antioxidant capabilities

“…In the context of biomedical applications, CeO 2 NPs have been studied for their redox enzyme mimetic efficiency and biocompatibility. 15–20 The redox properties of CeO 2 NPs are based on the reversible transition between Ce 4+ (defectless) and Ce 3+ (oxygen vacancy) states within its cubic fluorite structure ( Fm 3̄ m ), both states having significant populations in CeO 2 NPs due to their propensity for oxygen vacancies. The antioxidant properties of CeO 2 NPs in the presence of ROS ( • O − 2 , H 2 O 2 ) occurs through the oxidation of surface Ce 3+ states, as described by the following equations:Ce 3+ + • O 2 − + 2H + → Ce 4+ + H 2 O 2 2Ce 3+ + H 2 O 2 + 2H + → 2Ce 4+ + 2H 2 O…”