ACS Nano
·
2025
·
IF 16
Shuo Wang,Yuequan Wang,Yantong Li,Xiaoxue Lai,Miao Hu,Meng Chen,Cong Li,Xinrong Liu,Yanzhi Song,Yihui Deng
Inflammation-related immune cell subsets with abnormal activation, impaired tolerance, and complex intercellular interactions drive the progression and incurability of autoimmune diseases (AIDs). Here, we present an antigen-free nanovaccine-enabled holo-immunotherapy that comprehensively modulates inflammation, innate immunity, and adaptive immunity. The nanovaccine, composed of dual NF-κB inhibitors (budesonide and bortezomib) and comodified with sialic acid (SA) and enzyme-cleavable polyethylene glycol (PEG), leverages the SA-Siglec axis for targeted delivery to inflammation-related macrophage, dendritic cell, and CD4+ T cell subsets. By bridging innate and adaptive immunity, this multitargeted strategy synergistically reshapes the inflammatory microenvironment, establishes robust memory immune tolerance, and promotes immune homeostasis restoration, leading to sustained efficacy and delayed relapse in the collagen-induced arthritis (CIA) mouse model. Unlike traditional vaccines, the antigen-free design eliminates reliance on exogenous antigens, minimizes off-target immune risks, and holds promise for broader clinical applicability. The nanovaccine outperforms anti-TNF-α antibodies in treating models of CIA, adjuvant-induced arthritis, and chronic ulcerative colitis, highlighting its potential as a universal vaccine platform for AID therapy. Overall, this work provides a strategy to address AID challenges through precise immune regulation and durable therapeutic benefits.
研究领域:
免疫学
·
纳米医学
·
转化医学
·
自身免疫病治疗
·
分子药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Acta Biomaterialia
·
2022
·
IF 10.633
Hongdan Lu,Shengnan Li,Dongwei Dai,Qi Zhang,Zhiyi Min,Chuanzhou Yang,Shanbo Sun,Lu Ye,Chuanhui Teng,Xiang Cao,Haoyuan Yin,Lingyan Lv,Wei Lv,Hongliang Xin
Reperfusion injury is one of the major causes of disability and death caused by ischemic stroke, and drug development focuses mainly on single neuron protection. However, different kinds of cells in the neurovascular units (NVUs), including neurons, microglia and vascular endothelial cells, are pathologically changed after cerebral ischemia–reperfusion injury, resulting in an urgent need to develop a drug delivery system to comprehensively protect the kinds of cells involved in the NVU. Herein, we have constructed a c(RGDyK) peptide modified, NF-κB inhibitor caffeic acid phenethyl ester (CAPE)-loaded and reactive nitrogen species (RNS) stimuli-responsive liposomal nanocarrier (R-Lipo-CAPE) to target ischemic lesions and then remodel the NVU to reduce the progression of cerebral ischemia–reperfusion injury. The R-Lipo-CAPE liposomes were approximately 170 nm with a zeta potential of -30.8 ± 0.2 mV. The in vitro CAPE release behavior from R-Lipo-CAPE showed an RNS-dependent pattern. For in vivo studies, transient middle cerebral artery occlusion/reperfusion (MCAO) model mice treated with R-Lipo-CAPE had the least neurological impairment and decreased brain tissue damage, with an infarct area of 13%, compared with those treated with saline of 53% or free CAPE of 38%. Furthermore, microglia in the ischemic brain were polarized to the tissue-repairing M2 phenotype after R-Lipo-CAPE treatment. In addition, R-Lipo-CAPE-treated mice displayed a prominent down-regulated expression of MMP-9 and restored expression of the tight junction protein claudin-5. This proof-of-concept indicates that R-Lipo-CAPE is a promising nanomedicine for the treatment of cerebral ischemia–reperfusion injury through the regulation of neurovascular units. Statement of significance Based on the complex mechanism and difficulty in treatment of cerebral ischemia-reperfusion injury, the overall regulation of neurovascular unit has become an extremely important target. However, little nanomedicine has been directed to remodel the neurovascular units in targeted cerebral ischemia-reperfusion injury therapy. Here, c(RGDyK) peptide modified reactive nitrogen species (RNS) stimuli-responsive liposomal nanocarrier loaded with a NF-κB inhibitor (CAPE), was designed to simultaneously regulate various cells in the microenvironment of cerebral ischemia-reperfusion injury to remodel the neurovascular units. Our in vitro and in vivo data showed that the intelligent nanocarrier exerted the ability of pathological signal stimuli-responsive drug release, cerebral ischemia-reperfusion injury site targeting and neurovascular units remodeling through reducing neuron apoptosis , regulating microglia polarization and repairing vascular endothelial cell. Overall, the intelligent liposomal drug delivery system was a promising and safe nanomedicine in the perspective of cerebral ischemia-reperfusion injury treatment.
研究领域:
药理学
·
神经科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULAR PHARMACOLOGY
·
2025
·
IF 3
Shixin Li,Jingyan Wei,Shaofen Zhou,Shuaiqi Ma,Peihang Jiang,Jian He
The rise of drug-resistant influenza A virus (IAV) strains and severe lung injury caused by excessive inflammation highlight the need for new antivirals that combine antiviral and immunomodulatory effects. Adamantane, an established anti-IAV agent, targets the viral M2 matrix protein, but widespread mutations have limited its clinical utility. Previously, we identified that 2,5-dihydroxybenzylalcohol and its derivatives possess anti-IAV activity. In this study, we synthesized a series of adamantane-2,5-dihydroxy-benzylalcohol derivatives via reductive amination. Among these, Amt-1 demonstrated strong antiviral activity against both amantadine-sensitive (H1N1 PR8) and clinical isolates IAV strains (-log IC 50 =6.12–6.51 M). Mechanistic analyses, including immunofluorescence, ITC, qPCR, ELISA, luciferase assays, and Western blotting, revealed that Amt-1 not only interacts with the peptide segment of M2 ion channel protein (-log Kd = 5.08 M) but also activates Nrf2, leading to increased HO-1 expression and reduced production of pro-inflammatory cytokines IL-6, IL-1β, and TNF-α. Additionally, Amt-1 inhibited IAV-induced NF-κB activation, thereby suppressing viral replication. In vivo , Amt-1 reduced lung viral titers and mitigated histopathological damage in mice, surpassing amantadine in controlling inflammation and increased survival to 33%. In summary, Amt-1 is the first adamantane derivative shown to exert anti-IAV effects by modulating Nrf2/HO-1-mediated anti-inflammatory pathways and NF-κB-driven antiviral responses, while retaining M2 ion channel inhibition. This host-directed mechanism addresses drug resistance and limits immunopathology, making Amt-1 a promising therapeutic candidate for resistant influenza infections.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Science Advances
·
2020
·Vol. 6
·期 6
·
IF 13.117
Zecong Xiao,Zhenwei Su,Shisong Han,Jinsheng Huang,Liteng Lin,Xintao Shuai
The response to programmed cell death protein-1 (PD-1)/programmed death ligand-1 (PD-L1) blockade in cancer immunotherapy is limited because of multiple immune evasion mechanisms. Here, a previously unknown strategy is proposed to synergize the nuclear factor κB (NF-κB) inhibition and PD-1 blockade for antitumor immunotherapy. A dual pH-sensitive nanocarrier loading curcumin (CUR) and anti–PD-1 monoclonal antibody (aPD-1) may bind to circulating PD-1+ T cells and then follow their infiltration into the tumor. Furthermore, the nanodrug bound to PD-1+ T cells may be released in the tumor microenvironment, leaving aPD-1 to block PD-1 on T cells and generating a CUR-encapsulated cationic nanodrug that can be easily taken up by tumor cells/tumor associated macrophages (TAMs). Thus, not only the antitumor T cells mediate efficient CUR delivery to tumor but also the efficient CUR delivery promotes the tumor infiltration of antitumor T cells, thereby resulting in effective activation of antitumor immunity.
研究领域:
癌症免疫疗法
·
纳米技术
·
免疫学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2015
·
IF 4.383
Zhenzhen Liu,Haijun Gong,Rui Zeng,Xuan Liang,Li-Ming Zhang,Liqun Yang,Yuqing Lan
A hyperbranched cationic polysaccharide derivative-mediated small interfering (si)RNA interference strategy was proposed to inhibit nuclear transcription factor-kappa B (NF-κB) activation in human retinal pigment epithelial (hRPE) cells for the gene therapy of diabetic retinopathy. Two hyperbranched cationic polysaccharide derivatives containing the same amount of cationic residues, but with different branching structures and molecular weights, including 3-(dimethylamino)-1-propylamine-conjugated glycogen (DMAPA-Glyp) and amylopectin (DMAPA-Amp) derivatives, were developed for the efficient delivery of NF-κB siRNA into hRPE cells. The DMAPA-Glyp derivative showed lower toxicity against hRPE cells. Furthermore, the DMAPA-Glyp derivative more readily condensed siRNA and then formed the nanoparticles attributed to its higher branching architecture when compared to the DMAPA-Amp derivative. Both DMAPA-Glyp/siRNA and DMAPA-Amp/siRNA nanoparticles were able to protect siRNA from degradation by nuclease in 25% fetal bovine serum. The particle sizes of the DMAPA-Glyp/siRNA nanoparticles (70–120 nm) were smaller than those of the DMAPA-Amp/siRNA nanoparticles (130–180 nm) due to the higher branching architecture and lower molecular weight of the DMAPA-Glyp derivative. In addition, the zeta potentials of the DMAPA-Glyp/siRNA nanoparticles were higher than those of the DMAPA-Glyp/siRNA nanoparticles. As a result, siRNA was much more efficiently transferred into hRPE cells using the DMAPA-Glyp/siRNA nanoparticles rather than the DMAPA-Amp/siRNA nanoparticles. This led to significantly high levels of suppression on the expression levels of NF-κB p65 messenger RNA and protein in the cells transfected with DMAPA-Glyp/siRNA nanoparticles. This work provides a potential approach to promote hyperbranched polysaccharide derivatives as nonviral siRNA vectors for the inhibition of NF-κB activation in hRPE cells.
研究领域:
药理学
·
分子生物学
·
眼科学
·
基因治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
·
2023
·
IF 6.7
Jian Cai,Li Gao,Yue Wang,Yuanteng Zheng,Xiuling Lin,Pingzheng Zhou,Chunmei Chen,Kechun Liu,Lan Tang,Yonghong Liu,Yanhui Tan,Meng Jin,Xuefeng Zhou
Thirteen new sirenin derivatives named eupenicisirenins C–O ( 1 – 13 ), along with a biosynthetically related known one ( 14 ), were isolated from the mangrove sediment-derived fungus Penicillium sp. SCSIO 41410. The structures, which possessed a rare cyclopropane moiety, were confirmed by extensive analyses of the spectroscopic data , quantum chemical calculations , and X-ray diffraction. Among them, eupenicisirenin C ( 1 ) exhibited the strongest NF- κ B inhibitory activities, as well as suppressing effects on cGAS-STING pathway. Moreover, 1 showed the significant inhibitory effect on RANKL-induced osteoclast differentiation in bone marrow macrophages cells, and also displayed the therapeutic potential on prednisolone-induced zebrafish osteoporosis. Transcriptome analysis and the following verification tests suggested that its anti-osteoporotic mechanism is related to the extracellular matrix receptor interaction-related pathways. This study provided a promising marine-derived anti-osteoporotic agent for the treatment of skeletal disease.
研究领域:
海洋生物学
·
药理学
·
生物化学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2025
·
IF 19
Wanting Xue,Weihan Zheng,Huihui Zhang,Jiaxin Yang,Wenfeng Deng,Zhenning Dai,Ke Liu,Yunyun Chen,Xinyi Yun,Jiaying Li,Shiyu Li,Wenhua Huang
Reperfusion therapy for acute myocardial infarction is limited by myocardial ischemia-reperfusion injury (MIRI). MIRI is primarily mediated by oxidative stress in cardiomyocytes, exacerbated by M1 macrophages in the inflammatory microenvironment. Synergistic therapies targeting cardiomyocytes with antioxidants and M1 macrophages with anti-inflammatories have shown significant potential. Mitochondrial dysfunction is a unifying target for both cell types in MIRI; however, current nanoplatforms cannot simultaneously target them. Mito Q@MMNv is designed as a dual-targeting nanovesicle for cardiomyocytes and macrophages. It scavenges reactive oxygen species in cardiomyocytes while restoring oxidative phosphorylation in M1 macrophages through cell-selective metabolic reprogramming. In vivo, Mito Q@MMNv improves cardiac function and the inflammatory microenvironment: left ventricular ejection fraction increases by 62%, and the M1/M2 ratio shifts (delta cells increase 1.9-fold). Synergistic activation of Keap1 and inhibition of NF-κB attenuate inflammatory cascades while enhancing endogenous antioxidant defenses. Thus, this nano-engineered platform offers an immunomodulatory therapy for inflammation control and tissue repair in MIRI, providing new insights into cardiovascular nanomedicine.
研究领域:
心血管纳米医学
·
免疫调节治疗
·
代谢工程
·
活性氧清除
·
炎症调控
✓ 已验证
产品关联
DOI
高影响因子
Advanced Healthcare Materials
·
2024
·
IF 10
Xiaoliu Liang,Linyu Ding,Jiaxin Ma,Jiwei Li,Lei Cao,Hui Liu,Minglei Teng,Zhenjie Li,Yisheng Peng,Hu Chen,Yali Zheng,Hongwei Cheng,Gang Liu
The persistent challenge of healing infectious wounds and the rise of bacterial resistance represent significant hurdles in contemporary medicine. In this study, based on the natural small molecule drug Rhein self-assembly to form hydrogels and coordinate assembly with silver ions (Ag + ), a sustained-release carrier-free hydrogel with compact structure is constructed to promote the repair of bacterial-infected wounds. As a broad-spectrum antimicrobial agent, Ag + can avoid the problem of bacterial resistance caused by the abuse of traditional antibiotics. In addition, due to the slow-release properties of Rhein hydrogel, continuous effective concentration of Ag + at the wound site can be ensured. The assembly of Ag + and Rhein makes the hydrogel system with enhanced mechanical stability. More importantly, it is found that Rhein effectively promotes skin tissue regeneration and wound healing by reprogramming M1 macrophages into M2 macrophages. Further mechanism studies show that Rhein realizes its powerful anti-inflammatory activity through NRF2/HO-1 activation and NF-κB inhibition. Thus, the hydrogel system combines the excellent antibacterial properties of Ag + with the excellent anti-inflammatory and tissue regeneration ability of Rhein, providing a new strategy for wound management with dual roles.
研究领域:
材料科学
·
药剂学
·
生物医学工程
·
伤口愈合
·
药物递送系统
·
抗菌剂
·
炎症
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2025
·
IF 11.5
Danlei Hu,Dongmei Chen,Aoxue Zhang,Kuiyu Meng,Min Chen,Raja Mubbashar,Wei Qu,Shuyu Xie
Current IBD therapies face limitations such as systemic toxicity, off-target effects, and microbiota dysbiosis. We developed an oral multifunctional gel bead integrating three innovations: (1) a butyrate–apigenin synergy that inhibits NF-κB via CK2/p65 phosphorylation suppression, activates a PPAR-γ-mediated metabolic shift to β-oxidation, and modulates the microbiota by enhancing Bacteroidetes/suppressing Enterobacteriaceae; (2) an apigenin–butyrate ester prodrug overcoming organoleptic issues while enabling CK2 targeting; and (3) a pH/enzyme–responsive delivery system using the FDA-approved ascorbyl palmitate/alginate, achieving gastric protection, charge–mediated colitis targeting, and esterase–triggered release. In colitis model mice, gel beads restore clinical parameters, intestinal integrity, and microbial balance, outperforming apigenin-butyrate ester and 5-ASA at half-doses with extended intervals. It significantly downregulated colon CK2 expression (4.07-fold) and the phospho-P65/total P65 ratio (3.04-fold). This integrated strategy combining multimodal drug actions and precision delivery establishes a new paradigm for efficient and alternative IBD therapeutics with reduced dosing requirements.
研究领域:
药学
·
胃肠病学
·
药物递送
·
分子医学
·
微生物组研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY
·
2015
·
IF 2.084
Juanli Fu,Qiong Shi,Xiufang Song,Xiaomin Xia,Chuanyang Su,Zixuan Liu,Erqun Song,Yang Song
Tetrachlorobenzoquinone (TCBQ) is a joint metabolite of persistent organic pollutants (POPs), hexachlorobenzene (HCB) and pentachlorophenol (PCP). Previous studies have been reported that TCBQ contributes to acute hepatic damage due to its pro-oxidative nature. In the current study, TCBQ showed the highest capacity on the cytotoxicity, ROS formation and inflammatory cytokines release among four compounds, i.e., HCB, PCP, tetrachlorohydroquinone (TCHQ, reduced form of TCBQ) and TCBQ, in PC 12 cells. Further mechanistic study illustrated TCBQ activates nuclear factor-kappa B (NF-κB) signaling. The activation of NF-κB was identified by measuring the protein expressions of inhibitor of nuclear factor kappa-B kinase (IKK) α/β, p-IKKα/β, an inhibitor of NF-κB (IκB) α, p-IκBα, NF-κB (p65) and p-p65. The translocation of NF-κB was assessed by Western blotting of p65 in nuclear/cytosolic fractions, electrophoretic mobility shift assay (EMSA) and luciferase reporter gene assay. In addition, TCBQ significantly induced protein and mRNA expressions of inflammatory cytokines and mediators, such as interleukin-1 beta (IL-1β), IL-6, tumor necrosis factor-alpha (TNF-α), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and the production of nitric oxide (NO) and prostaglandin E2 (PGE2). Pyrrolidine dithiocarbamate (PDTC), a specific NF-κB inhibitor inhibited these effects efficiently, further suggested TCBQ-induced inflammatory responses involve NF-κB signaling. Moreover, antioxidants, i.e., N-acetyl- l -cysteine (NAC), Vitamin E and curcumin, ameliorated TCBQ-induced ROS generation as well as the activation of NF-κB, which implied that ROS serve as the upstream molecule of NF-κB signaling. In summary, TCBQ exhibits a neurotoxic effect by inducing oxidative stress-mediated inflammatory responses via the activation of IKK/IκB/NF-κB pathway in PC12 cells.
研究领域:
毒理学
·
神经科学
·
细胞生物学
·
药理学
✓ 已验证
DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2018
·
IF 2.559
Fan Zhang,Chenhong Zhang
Intracerebral hemorrhage (ICH) is reported as a common and often fatal type of stroke accompanied with high morbidity and mortality, and it frequently results in long-lasting neurological dysfunctions. However, the pathogenesis that contributes to ICH has not been fully understood. Rnf112, also known as Znf179, is a member of the RING finger protein family. The expression of Rnf112 is abundant in the brain and is modulated during brain progression and development. The study aimed to explore the role of Rnf112 in brain injury after ICH, as well as the underlying molecular mechanisms. The results indicated that ICH led to a significant decrease in Rnf112, which was confirmed in oxyhemoglobin (oxyHb)-incubated astrocytes and microglial cells. Moreover, the Rnf112 knockout (Rnf112 −/− ) mice and wild type (WT) mice induced by ICH were further employed. Compared to the WT/ICH group, Rnf112 −/− mice exhibited accelerated brain injury, as evidenced by the increased brain water contents and neurological deficit scores (NDS). In comparison to WT/ICH group, a remarkable up-regulation in the release of pro-inflammatory cytokines, including tumor necrotic factor-α (TNF-α), interleukin-6 (IL-6), and IL-1β, was observed in perihematoma tissues of Rnf112 −/− mice on day 3 post-ICH. The process was along with promoted glial fibrillary acidic protein (GFAP) and Iba1 expression and reduced NeuN levels. Furthermore, ICH-induced increases in toll-like receptor (TLR)-4 and myeloid differentiation primary response protein (MyD88) expression were exacerbated by the loss of Rnf112. The phosphorylated expression of IKKα, inhibitor of NF-κB (IκBα) and nuclear factor-kappa B (NF-κB) induced by ICH in perihematoma tissues of mice was markedly enhanced in Rnf112 −/− mice. Rnf112 repression-induced inflammatory response was verified in lipopolysaccharide (LPS)-incubated glial cells . In contrast, over-expressing Rnf112 markedly attenuated ICH-induced brain injury by restraining inflammation via inactivating TLR-4/NF-κB pathway. In summary, our findings suggested that Rnf112 expression was highly involved in the progression of ICH, and targeting Rnf112 signaling might be a promising therapeutic strategy against ICH development.
研究领域:
神经科学
·
分子生物学
·
病理学
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）