An ROS-responsive artesunate prodrug nanosystem co-delivers dexamethasone for rheumatoid arthritis treatment through the HIF-1α/NF-κB cascade regulation of ROS scavenging and macrophage repolarization

Li, Yifan; Liang, Qiangwei; Zhou, Liyue; Cao, Yong; Yang, Jiayu; Li, Juan; Liu, Jinxia; Bi, Jiawei; Liu, Yanhua

doi:10.1016/j.actbio.2022.08.054

Cited by 73 publications

(22 citation statements)

References 33 publications

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“…Here we created a collagen-induced arthritis (CIA) model in Wistar rat by injecting incomplete Freund's adjuvant and bovine collagen subcutaneously (Figure 5B) and then analyzed the therapeutic impact of micelles following intraarticular injection. 41 We first evaluated the distribution of micelles in CIA mice by monitoring the changes in the fluorescence of intraarticularly injected ICG-HA@RH-CeO X using an IVIS imaging system 42 (Figure S10A). The micelles began to degrade at steady rates after injection into the joints and some fluorescence remained after 3 days of incubation, suggesting that TK linker breakage at high ROS levels facilitates localized drug release.…”

Section: Resultsmentioning

confidence: 99%

Redox Homeostasis Strategy for Inflammatory Macrophage Reprogramming in Rheumatoid Arthritis Based on Ceria Oxide Nanozyme-Complexed Biopolymeric Micelles

Zhou

Chen

et al. 2023

ACS Nano

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The synovial tissues under rheumatoid arthritis conditions are usually infiltrated by inflammatory cells, particularly M1 macrophages with aberrant redox homeostasis, which causes rapid deterioration of articular structure and function. Herein, we created an ROS-responsive micelle (HA@RH-CeO X ) through the in situ host–guest complexation between ceria oxide nanozymes and hyaluronic acid biopolymers, which precisely delivered nanozyme and clinically approved rheumatoid arthritis drug Rhein (RH) to proinflammatory M1 macrophage populations in inflamed synovial tissues. The abundant cellular ROS could cleave the thioketal linker to trigger the release of RH and Ce. Specifically, the Ce3+/Ce4+ redox pair could present SOD-like enzymatic activity to rapidly decompose ROS and alleviate the oxidative stress in M1 macrophages, while RH could inhibit the TLR4 signaling in M1 macrophages, both of which could act in a concerted manner to induce their repolarization into anti-inflammatory M2 phenotype to ameliorate local inflammation and promote cartilage repair. Notably, rats bearing rheumatoid arthritis showed a drastic increase in the M1-to-M2 macrophage ratio from 1:0.48 to 1:1.91 in the inflamed tissue and significantly reduced inflammatory cytokine levels including TNF-α and IL-6 following the intra-articular injection of HA@RH-CeO X , accompanied by efficient cartilage regeneration and restored articular function. Overall, this study revealed an approach to in situ modulate the redox homeostasis in inflammatory macrophages and reprogram their polarization states through micelle-complexed biomimetic enzymes, which offers alternative opportunities for the treatment of rheumatoid arthritis.

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Section: Resultsmentioning

confidence: 99%

Redox Homeostasis Strategy for Inflammatory Macrophage Reprogramming in Rheumatoid Arthritis Based on Ceria Oxide Nanozyme-Complexed Biopolymeric Micelles

Zhou

Chen

et al. 2023

ACS Nano

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“…Anionic HA-containing NPs LSECs, Tregs Suppressing antigen-specific immune responses [29] AB diblock copolymers NPs LSECs, KCs Leading to immune inflammation [33] Stab2-containing NPs LSECs, Tregs Clearing of lipoproteins [30] Mannose-modified albumin NPs Macrophages TGFβ-siRNA to CD206 + as an anti-fibrotic strategy [37] CMC-containing NPs Macrophages Reducing host immune response [40] PS-containing NPs Macrophages Reducing collagen fiber deposition [42] silk or silicon-containing NPs Macrophages Pro-inflammatory phenotype [69] hydrogel particles M2-polarized macrophages Improving immunocompromised and impaired angiogenesis [108,109] DEX/HA-TK-ART PMs M2-polarized macrophages HIF-1α/NF-κB signaling cascade [90] mLNP-siHMGB1 Macrophages, HSCs Inhibiting the activation of HSCs [38] DSPE-PEG-CeO2 NPs Macrophages, HSCs Reducing inflammation [86] CNF HSCs, macrophages Increasing glycolysis and reprogramming and reducing initiated inflammatory [70] VA-SLNs HSCs Reducing PPARγ/SREBPs-mediated lipid accumulation [61] CS sulfate PMs HSCs Anti-fibrotic strategy [63] CS-coated green silver NPs HSCs Bounding to the fibrogenic protein TGF-β [65] hydrogels HSCs Blocking the TGF-β1/Smad pathway [66] RGD HSCs Inhibiting the proliferation of HSCs [82] Chol-PCX/miRNA NPs HSCs, T cells Disrupting the lipid metabolic network [73,74] GQD HSCs Inhibiting lipid peroxidation, apoptosis, and autophagy [87] CeO2 NPs HSCs Antioxidant effect [85] FPL HSCs Antioxidant effect [88] ChiBil carrying losartan HSCs attenuating iron death [89] PEG-PLGA-containing NPs LSECs, hepatocytes and HSCs Constricting abnormal blood vessels, reducing MVD [99] Self-assembled PMs LSECs, hepatocytes and HSCs Avoiding the hepatotoxicity and side effects [96] NPs laponite HUVECs enhancing HIF-1α and VEGF expression, accelerating neovascularization [110] and mannose receptors (MR) that produce inhibitory acquired immune responses. LSECs regulate adaptive immune responses directly by presenting antigens to T cells and also regulate natural killer T cells (NKT cells) by expressing CXCL16, and the cell surface ligand for CXCR6…”

Section: Np Typementioning

confidence: 99%

“…A chitosanbilirubin micelle (ChiBil) carrying losartan attenuates iron death due to iron-catalyzed lipid peroxide (LPO) accumulation in liver fibrosis [89]. ROS-responsive DEX/ HA-TK-ART PMs induce M2 macrophages via HIF-1α/ NF-κB signaling cascade [90]. In addition, in hepatocellular carcinoma, a two-pronged approach of T-SPNAPt/ NO-enhanced damage-blocking repair, a reactive nitrogen species (RNS)-generating system, was developed to achieve efficient treatment [91] (Table 2).…”

Section: Engineered Nps Regulated Hypoxia-associated Microenvironmentmentioning

confidence: 99%

Remodeling the hepatic fibrotic microenvironment with emerging nanotherapeutics: a comprehensive review

et al. 2023

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Liver fibrosis could be the last hope for treating liver cancer and remodeling of the hepatic microenvironment has emerged as a strategy to promote the ablation of liver fibrosis. In recent years, especially with the rapid development of nanomedicine, hepatic microenvironment therapy has been widely researched in studies concerning liver cancer and fibrosis. In this comprehensive review, we summarized recent advances in nano therapy-based remodeling of the hepatic microenvironment. Firstly, we discussed novel strategies for regulatory immune suppression caused by capillarization of liver sinusoidal endothelial cells (LSECs) and macrophage polarization. Furthermore, metabolic reprogramming and extracellular matrix (ECM) deposition are caused by the activation of hepatic stellate cells (HSCs). In addition, recent advances in ROS, hypoxia, and impaired vascular remodeling in the hepatic fibrotic microenvironment due to ECM deposition have also been summarized. Finally, emerging nanotherapeutic approaches based on correlated signals were discussed in this review. We have proposed novel strategies such as engineered nanotherapeutics targeting antigen-presenting cells (APCs) or direct targeting T cells in liver fibrotic immunotherapy to be used in preventing liver fibrosis. In summary, this comprehensive review illustrated the opportunities in drug targeting and nanomedicine, and the current challenges to be addressed. Graphical Abstract

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“…Additionally, a mannose receptor, cluster of differentiation (CD) 206, is upregulated in response to inflammation, which allows for targeted delivery of therapeutic agents to macrophages at inflammatory sites . Thus, targeted macrophage reprogramming from M1 to M2 could serve as a promising approach for inflammation alleviation. − …”

Section: Introductionmentioning

confidence: 99%

Macrophage Reprogramming via Targeted ROS Scavenging and COX-2 Downregulation for Alleviating Inflammation

et al. 2023

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Inflammation-related diseases affect large populations of people in the world and cause substantial healthcare burdens, which results in significant costs in time, material, and labor. Preventing or relieving uncontrolled inflammation is critical for the treatment of these diseases. Herein, we report a new strategy for alleviating inflammation by macrophage reprogramming via targeted reactive oxygen species (ROS) scavenging and cyclooxygenase-2 (COX-2) downregulation. As a proof of concept, we synthesize a multifunctional compound named MCI containing a mannose-based macrophage targeting moiety, an indomethacin (IMC)-based segment for inhibiting COX-2, and a caffeic acid (CAF)-based section for ROS clearance. As revealed by a series of in vitro experiments, MCI could significantly attenuate the expression of COX-2 and the level of ROS, leading to M1 to M2 macrophage reprogramming, as evidenced by the reduction and the elevation in the levels of pro-inflammatory M1 markers and anti-inflammatory M2 markers, respectively. Furthermore, in vivo experiments show MCI′s promising therapeutic effects on rheumatoid arthritis (RA). Our work illustrates the success of targeted macrophage reprogramming for inflammation alleviation, which sheds light on the development of new anti-inflammatory drugs.

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An ROS-responsive artesunate prodrug nanosystem co-delivers dexamethasone for rheumatoid arthritis treatment through the HIF-1α/NF-κB cascade regulation of ROS scavenging and macrophage repolarization

Cited by 73 publications

References 33 publications

Redox Homeostasis Strategy for Inflammatory Macrophage Reprogramming in Rheumatoid Arthritis Based on Ceria Oxide Nanozyme-Complexed Biopolymeric Micelles

Redox Homeostasis Strategy for Inflammatory Macrophage Reprogramming in Rheumatoid Arthritis Based on Ceria Oxide Nanozyme-Complexed Biopolymeric Micelles

Remodeling the hepatic fibrotic microenvironment with emerging nanotherapeutics: a comprehensive review

Macrophage Reprogramming via Targeted ROS Scavenging and COX-2 Downregulation for Alleviating Inflammation

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