Immune-regulating strategy against rheumatoid arthritis by inducing tolerogenic dendritic cells with modified zinc peroxide nanoparticles

Abstract

In hypoxic dendritic cells (DCs), a low level of Zn2+ can induce the activation of immunogenic DCs (igDCs), thereby triggering an active T-cell response to propel the immune progression of rheumatoid arthritis (RA). This finding indicates the crucial roles of zinc and oxygen homeostasis in DCs during the pathogenesis of RA. However, very few studies have focused on the modulation of zinc and oxygen homeostasis in DCs during RA treatment. Proposed herein is a DC-targeting immune-regulating strategy to induce igDCs into tolerogenic DCs (tDCs) and inhibit subsequent T-cell activation, referred to as ZnO2/Catalase@liposome-Mannose nanoparticles (ZnCM NPs). ZnCM NPs displayed targeted intracellular delivery of Zn2+ and O2 towards igDCs in a pH-responsive manner. After inactivating OTUB1 deubiquitination, the ZnCM NPs promoted CCL5 degradation via NF-κB signalling, thereby inducing the igDC-tDC transition to further inhibit CD4+ T-cell homeostasis. In collagen-induced arthritis (CIA) mice, this nanoimmunoplatform showed significant accumulation in the spleen, where immature DCs (imDCs) differentiated into igDCs. Splenic tDCs were induced to alleviate ankle swelling, improve walking posture and safely inhibit ankle/spleen inflammation. Our work pioneers the combination of DC-targeting nanoplatforms with RA treatments and highlights the significance of zinc and oxygen homeostasis for the immunoregulation of RA by inducing tDCs with modified ZnO2 NPs, which provides novel insight into ion homeostasis regulation for the treatment of immune diseases with a larger variety of distinct metal or nonmetal ions. Graphical Abstract

Tailoring Biomaterials Ameliorate Inflammatory Bone Loss

“…Reproduced with permission. [169] Copyright 2022, Springer Nature. could promote activated M1 macrophages polarize into reprogrammed M2 macrophages with considerable efficiency (>90%) and prolonged duration (>3 days).…”

“…[171] Qiao et al effectively treated RA via ZnO NPs modified by DCs-targeting ligand mannose and catalase (named ZnCM NPs). [169] First, modified ZnO 2 accessed DCs in the spleen and released Zn 2+ and H 2 O 2 in the acidic environment of lysosomes. Subsequently, catalase catalyzed H 2 O 2 to create O 2 , which cooperated with Zn 2+ to induce tolerogenic DCs by facilitating CCL5 degradation via NF-𝜅B signaling pathway (Figure 7E).…”

“…Biomaterials inhibit inflammatory response by inducing tolerance in DCs or suppressing the function of mature DCs. [169,170] Tolerogenic DCs can be applied to cause immune tolerance via quelling the autoreactive lymphocytes. [171] Qiao et al effectively treated RA via ZnO NPs modified by DCs-targeting ligand mannose and catalase (named ZnCM NPs).…”

“…E) Schematic illustration of ZnCM NPs-induced tolerogenic DCs for treating RA. Reproduced with permission [169]. Copyright 2022, Springer Nature.…”

Epimedii Herba: An ancient Chinese herbal medicine in the prevention and treatment of rheumatoid arthritis

“…A recent study showed that synovial microenvironment in RA was responsible for DCs maturation and metabolic reprogramming via up-regulating STAT3 activation ( Canavan et al, 2020 ). In addition, intracellular Zn 2+ homeostasis and low oxygen state also impacted the maturation of DCs ( Qiao et al, 2022 ). Inhibition of DCs maturation is an important treatment of DC-targeting in RA.…”