Synergistically targeting synovium STING pathway for rheumatoid arthritis treatment

Shen, Haotian; Jin, Lai; Zheng, Qiangqiang; Ye, Ziqiang; Cheng, Linxiang; Wu, Yuxu; Wu, Honghao; Jon, Tae Gyong; Liu, Wenduo; Pan, Zongyou; Mao, Zhengwei; Wang, Yue

doi:10.1016/j.bioactmat.2022.12.001

Cited by 19 publications

(18 citation statements)

References 71 publications

(85 reference statements)

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“…Though more recent STING agonists such as ADU-S100 and diABZI exhibit great pharmacokinetic profiles and biostability with promising preclinical tumor therapeutic efficacy, their therapeutic efficacy and safety remain to be fully examined preclinically and clinically. Here, we summarize our recent attempt to advance the drug development for cGAS-STING immunomodulation by approaches such as novel drug delivery systems and targeting cGAS, instead of directly targeting STING, for the immunotherapy of cancer and autoimmune disorders . In some examples, we developed physiologically responsive drug delivery systems for efficient delivery and conditional release of STING agonists in robust cancer immunotherapy.…”

Section: Discussionmentioning

confidence: 99%

“…Here, we summarize our recent attempt to advance the drug development for cGAS-STING immunomodulation by approaches such as novel drug delivery systems and targeting cGAS, instead of directly targeting STING, for the immunotherapy of cancer and autoimmune disorders. 75 In some examples, we developed physiologically responsive drug delivery systems for efficient delivery and conditional release of STING agonists in robust cancer immunotherapy. Moreover, the drug development of CDNs, such as 2′3′-cGAMP, is largely limited by its limited biostability and poor cytosolic delivery.…”

Section: Cgas-inhibiting Drug Delivery Systems For Ra Immunotherapymentioning

confidence: 99%

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Engineering and Delivery of cGAS-STING Immunomodulators for the Immunotherapy of Cancer and Autoimmune Diseases

Zhou,

Cheng,

Zhang

et al. 2023

Acc. Chem. Res.

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The cyclic GMP-AMP synthase-stimulator interferon gene (cGAS-STING) pathway is an emerging therapeutic target for the prophylaxis and therapy of a variety of diseases, ranging from cancer, infectious diseases, to autoimmune disorders. As a cytosolic double stranded DNA (dsDNA) sensor, cGAS can bind with relatively long dsDNA, resulting in conformational change and activation of cGAS. Activated cGAS catalyzes the conversion of adenosine triphosphate (ATP) and guanosine triphosphate (GTP) into cGAMP, a cyclic dinucleotide (CDN). CDNs, including 2′3′-cGAMP, stimulate adapter protein STING on the endoplasmic membrane, triggering interferon regulatory factor 3 (IRF3) phosphorylation and nuclear factor kappa B (NF-κB) activation. This results in antitumor and antiviral type I interferon (IFN-I) responses. Moreover, cGAS-STING overactivation and the resulting IFN-I responses have been associated with a number of inflammatory and autoimmune diseases. This makes cGAS-STING appealing immunomodulatory targets for the prophylaxis and therapy of various related diseases. However, drug development of CDNs and CDN derivatives is challenged by their limited biostability, difficult formulation, poor pharmacokinetics, and inefficient tissue accumulation and cytosolic delivery. Though recent synthetic small molecular CDN-or non-CDN-based STING agonists have been reported with promising preclinical therapeutic efficacy, their therapeutic efficacy and safety remain to be fully evaluated preclinically and clinically. Therefore, it is highly desirable and clinically significant to advance drug development for cGAS-STING activation by innovative approaches, such as drug delivery systems and drug development for pharmacological immunomodulation of cGAS. In this Account, we summarize our recent research in the engineering and delivery of immunostimulatory or immunoregulatory modulators for cGAS and STING for the immunotherapy of cancer and autoimmune diseases. To improve the delivery efficiency of CDNs, we developed ionizable and pHresponsive polymeric nanocarriers to load STING agonists, aiming to improve the cellular uptake and facilitate the endosomal escape to induce efficient STING activation. We also codelivered STING agonists with complementary immunostimulatants in nanoparticle-in-hydrogel composites to synergetically elicit potent innate and adaptive antitumor responses that eradicate local and distant large tumors. Further, taking advantage of the simplicity of manufacturing and the established nucleic acid delivery system, we developed oligonucleotide-based cGAS agonists as immunostimulant immunotherapeutics as well as adjuvants for peptide antigens for cancer immunotherapy. To suppress the overly strong proinflammatory responses associated with cGAS-STING overactivation in some of the autoimmune disorders, we devised nanomedicine-in-hydrogel (NiH) that codelivers a cGAS inhibitor and cell-free DNA (cfDNA)-scavenging cationic nanoparticles (cNPs) for systemic immunosuppression in rheumatoid arthritis (RA) therapy. Lastly, we di...

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Section: Discussionmentioning

confidence: 99%

Section: Cgas-inhibiting Drug Delivery Systems For Ra Immunotherapymentioning

confidence: 99%

Engineering and Delivery of cGAS-STING Immunomodulators for the Immunotherapy of Cancer and Autoimmune Diseases

Zhou,

Cheng,

Zhang

et al. 2023

Acc. Chem. Res.

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“…RA is a progressive and chronic systemic illness that causes gradual joint deterioration and impairment. Half of individuals with RA describe foot or ankle joint symptoms as the first presentation of the illness, and 71% of these patients acquire gait difficulty over time [16] . Regarding the baseline characteristics of the current study, a recent study came in line with ours, where it was carried out on 152 RA patients and 52 healthy controls.…”

Section: Discussionmentioning

confidence: 99%

Role of High-Resolution Grey Scale and Power Doppler Ultrasonography in Assessment of Ankle Joints of Symptomatic and Asymptomatic Rheumatoid Arthritis Patients

Yousef¹,

Abogamal²,

Khater³

et al. 2023

The Egyptian Journal of Hospital Medicine

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Background: Rheumatoid arthritis (RA) is a systemic autoimmune chronic inflammatory condition that may impact a variety of organs and tissues, but mostly targets flexible (synovial) joints. Objective: The aim of the current study was to assess influence of power Doppler ultrasound (PDUS) and high-resolution ultrasonography (US) in estimation of ankle joints abnormalities in patients suffering RA with or without ankle joint pain. Patients and methods: A cross sectional study was conducted on 100 participants presented with clinical diagnosis of RA, from the Rheumatology and Rehabilitation outpatient clinic of Al-Azhar University Hospitals. Participants were subjected to a comprehensive history, clinical examination by the referral to rheumatologist, laboratory tests, and high-resolution US and PDUS examination. Results: Patients with symptoms had a considerably higher Disease Activity Score in 28 joints (DAS 28) than those without symptoms (P<0.001). Patients without symptoms had a considerably greater prevalence of low DAS 28 scores (P<0.001), but high score was considerably greater in symptomatic individuals (P=0.007). Conclusion: US enables rapid identification and precise detection of joint and/or tendon inflammatory involvement at ankle level in individuals with RA. Clinicians should be recommended to utilize US more often to identify pathological ankle problems.

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“…In addition, upregulated pro-inflammatory factors prevent the maturation of osteoblasts [ 12 , 13 ] and induce high expression of RANKL on the macrophages, which will bind to RANK and activate osteoclasts to erode bone [ 14 , 15 ], resulting in gradual defect expansion and hindered regeneration. Thus, regulating the high ROS microenvironment and inhibiting macrophages inflammation is a crucial target for RA treatment [ 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

A dual dynamically cross-linked hydrogel promotes rheumatoid arthritis repair through ROS initiative regulation and microenvironment modulation-independent triptolide release

Wang,

Huang,

Fang

et al. 2024

Materials Today Bio

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Synergistically targeting synovium STING pathway for rheumatoid arthritis treatment

Cited by 19 publications

References 71 publications

Engineering and Delivery of cGAS-STING Immunomodulators for the Immunotherapy of Cancer and Autoimmune Diseases

Engineering and Delivery of cGAS-STING Immunomodulators for the Immunotherapy of Cancer and Autoimmune Diseases

Role of High-Resolution Grey Scale and Power Doppler Ultrasonography in Assessment of Ankle Joints of Symptomatic and Asymptomatic Rheumatoid Arthritis Patients

A dual dynamically cross-linked hydrogel promotes rheumatoid arthritis repair through ROS initiative regulation and microenvironment modulation-independent triptolide release

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