Nano Research
·
2018
·Vol. 11
·期 5
·2872-2884
·
IF 7.994
Iqbal Shoaib,Du Xiaojiao,Wang Jilong,Li Hongjun,Yuan Youyong,Wang Jun
Nanoparticle (NP) drug delivery systems have been successfully designed and implemented to orally deliver siRNAs for inflammatory disorders. However, the influence of surface charge on orally administered siRNA nanocarriers has not been investigated. In this study, we prepared structurally related poly(ethylene glycol)-block-poly(lactic-co-glycolic acid) (PEG 5K - b -PLGA 10K ) NPs with the assistance of a synthesized lipid featuring surface amine groups for subsequent charge tuning. NPs were prepared by a double emulsion method, and their surface charge could be tuned and controlled by a succinylation reaction to yield NPs with different surface charges, while maintaining their size and composition. The prepared NPs were termed as aminated NPs (ANPs), plain NPs (PNPs), or carboxylated NPs (CNPs) based on their surface charge. All NPs exhibited the desired structural stability and siRNA integrity after enzymatic degradation. In vivo studies showed that ANPs significantly accumulated in inflamed colons, and they were successful in decreasing TNF-α secretion and mRNA expression levels while maintaining colonic histology in a murine model of acute ulcerative colitis (UC). This study described a methodology to modify the surface charge of siRNA-encapsulating polymeric NPs and highlighted the influence of surface charge on oral delivery of siRNA for localized inflammatory disorders.
研究领域:
药学科学
·
纳米技术
·
炎症性疾病
·
药物递送系统
✓ 已验证
产品关联
DOI
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2025
·
IF 13.2
Cuihua Zhang,Yawen Yao,Wenqiu Xu,Jieying Zhou,Hua Yu,Ying Li,Wei Xiong
Efficient cytosolic delivery of small interfering RNA (siRNA) remains a challenge in RNA therapeutics, particularly for oral administration. Identifying new cytosolic stimulus-responsive targets is thus crucial for optimizing siRNA delivery. Given the elevated intracellular arginase-1 (Arg1) levels in inflamed colonic mucosa, we developed lipid nanoparticles (siRNA-LANPs) derived from L-arginine-modified chitosan (ACS) for the cytosolic release of TNF-α-siRNA to treat ulcerative colitis (UC). The siRNA-LANPs exhibited superior Arg1-binding affinity compared to its substrate, L-arginine, enabling rapid Arg1-responsive release. Moreover, we found that siRNA-LANPs maintained nanoparticle stability, and 84.5 % of the loaded siRNA remained intact in simulated digestive fluids over 12 h. Following oral administration, siRNA-LANPs efficiently penetrated the mucus layer and preferentially accumulated in inflamed colonic tissue compared to healthy colon tissue. In DSS-induced colitis mice, siRNA-LANPs significantly reduced disease severity through TNF-α silencing, achieving greater therapeutic efficacy than sulfasalazine (a first-line UC treatment). The siRNA-LANPs exhibited superior TNF-α silencing compared to transfection reagent Lipo3000 and TNF-α biologic agent infliximab. The enhanced performance was attributed to multiple endocytic pathways, improved lysosomal escape capability (29.7 %), and Arg1-mediated cytoplasmic siRNA release. In summary, Arg1 seems to be a promising intracellular target for stimulus-responsive, oral siRNA delivery in UC treatment.
研究领域:
RNA治疗
·
纳米医学
·
胃肠病学
·
药物递送
·
分子生物学
✓ 已验证
产品关联
DOI
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2025
·
IF 19
Qiaoxuan Wang,Qi Cheng,Ding Huang,Kefei Zhao,Qiaoju Hu,Min Liang,Yifan Xie,Huaxiang Wu,Changyou Gao
The inefficient lysosomal escape of small interfering RNA (siRNA) from immune cells remains a major barrier to therapeutic efficacy. To address this challenge, an innovative pH-triggered aggregation nanoplatform for enhanced siRNA delivery is developed. By using adamantane (Ad)-modified hyperbranched poly-L-lysine (HBPL-Ad) as a backbone, this nanoplatform incorporated acetalated β-cyclodextrin (β-ACD) as a pH-sensitive “gatekeeper”, together with siRNA to prepare physiologically stable aggregated nanoparticles (ANPs). Triggered by the acidic lysosomal microenvironment, the β-ACD hydrolysis exposed β-CD cavities to enable strong host-guest (β-CD/Ad) binding. This binding caused nanoparticle aggregation and subsequent mild lysosomal membrane permeabilization (LMP), facilitating efficient siRNA escape independent of the proton sponge effect. The ANPs demonstrated superior cellular uptake and significantly enhanced TNF-α silencing across macrophages, dendritic cells, and Jurkat immune cells in vitro. Intraperitoneal administration of ANPs loaded with TNF-α siRNA in a collagen-induced arthritis (CIA) model achieved 93% mRNA reduction and 95% protein reduction in joint TNF-α levels, significantly outperforming Lipo2000 (56% mRNA and 60% protein reduction), effectively attenuating synovitis and cartilage erosion without detectable systemic toxicity. This work establishes pH-triggered programmable aggregation as a potent and transformative strategy for overcoming immune cell delivery barriers, offering a promising clinically viable platform for RNAi-based immunotherapy.
研究领域:
纳米技术
·
RNA干扰
·
免疫治疗
·
药物递送系统
·
生物医学工程
✓ 已验证
产品关联
DOI
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2022
·Vol. 32
·期 44
·2206261
·
IF 19.924
Chao Li,Yawei Du,Hongzhi Lv,Jun Zhang,Pengzhen Zhuang,Wu Yang,Yingze Zhang,Juan Wang,Wenguo Cui,Wei Chen
Artemisinin and its derivatives (artemisinins) are first-line chemotherapeutic agents of lethal malaria, which also showed tremendous value in many other diseases including chronic inflammation. Unfortunately, almost all artemisinins are rapid-acting medicines with an extremely short half-life in vivo, which significantly limits their clinical application for these new adaptation diseases. In this study, a locally injectable long-acting gene/artemisinin co-delivery nano-microplex consisting of a biodegradable hyaluronic acid (HA) microsphere and releasable gene/artemisinin co-delivery nano-lipoplex is developed first, to obtain an improved efficacy for rheumatoid arthritis (RA). Briefly, a cationic multicomponent drug-embedded liposome with pharmacological activity is first reported based on two novel artemisinin derivatives (dAPC and dACC), which possess mimic phospholipids and cationic lipids, respectively. A cationic artemisinin-embedded lipoplex is first reported as a medicative gene carrier here. An in situ injectable TNF-α siRNA/artemisinin co-delivery nano-microplex (MTAsi@MG) is further prepared by immobilization of TNF-α siRNA/lipoplex on porous microfluidic HA microspheres. Using this nano-microplex for intra-articular injection, the sustaining activity of gene therapy and artemisinin efficacy for RA long-term treatment is first realized. Undoubtedly, this intra-articular injectable TNF-α siRNA/artemisinin co-delivery nano-microplex based on dAPC/dACC lipoplex and microfluidic microspheres would be one of the most potent gene/drug co-delivery systems for RA therapy.
研究领域:
药学
·
生物技术
·
纳米医学
·
风湿病学
·
分子生物学
✓ 已验证
DOI
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2021
·Vol. 31
·期 21
·2008960
·
IF 18.808
Jiandong Yang,Shanzhou Duan,Huan Ye,Chenglong Ge,Chunxian Piao,Yongbing Chen,Minhyung Lee,Lichen Yin
Pulmonary delivery of anti-inflammatory siRNA holds great potential in mitigating the cytokine storm during severe pneumonia. However, commonly utilized polycationic siRNA delivery vehicles can hardly penetrate the mucus barrier, thus greatly hurdling their therapeutic efficacy. Herein, TNF-α siRNA (siTNF-α) delivery nanocomplexes (NCs) are engineered with mucus/cytomembrane dual-penetration capabilities, realized via surface-coating of NCs with RC, an inflammation-sheddable, charge-reversal pro-peptide of RAGE-binding peptide (RBP). RC-coated dendritic poly- L -lysine/siTNF-α (DsT) NCs possess negative surface charges, and can thus efficiently penetrate the mucus layer after intratracheal administration. In the inflamed alveolar space with mild acidity, RC recovers to the cationic RBP and shed off, re-exposing the DsT NCs that efficiently transfect the alveolar macrophages and provokes TNF-α silencing. Thus, siTNF-α and RBP cooperatively alleviate the uncontrolled inflammation during acute lung injury. This study renders a unique approach for mediating trans-mucus nucleic acid delivery, and will find promising utilities for the treatment of severe pneumonia.
研究领域:
药剂学
·
纳米技术
·
肺科学
·
分子生物学
✓ 已验证
DOI
高影响因子
Biomaterials Science
·
2018
·Vol. 6
·期 7
·1986-1993
·
IF 5.831
Wenxin Zhang,Yang Zhou,Xudong Li,Xin Xu,Yongbing Chen,Rongying Zhu,Lichen Yin
As one of the intractable challenges in the clinic, the treatment of acute liver failure (ALF) is limited due to high mortality and resource cost. RNA interference (RNAi) provides a new modality for the anti-inflammatory therapy of ALF, while its therapeutic efficacy is greatly hampered by the lack of effective carriers to cooperatively overcome the various systemic barriers. Herein, we developed macrophage-targeting and reactive oxygen species (ROS)-responsive polyplexes to enable efficient systemic delivery of TNF-α siRNA (siTNF-α) to attenuate hepatic inflammation in mice bearing ALF. Se-PEI, obtained from the cross-linking of 600 Da polyethylenimine (PEI) via the ROS-responsive diselenide bond, was developed to condense siTNF-α, and the obtained polyplexes were further coated with carboxylated mannan (Man-COOH). Man-COOH coating allowed active targeting of polyplexes to macrophages with over-expressed mannose receptors (MRs), and it shielded the surface positive charges to enhance the serum stability of polyplexes. Se-PEI could be degraded by ROS in inflammatory macrophages to promote intracellular siRNA release to potentiate the gene knockdown efficiency, and in the meantime reduce the material cytotoxicity associated with high molecular weight. As such, i.v. injected Man-COOH/Se-PEI/siTNF-α polyplexes afforded notable TNF-α silencing by ∼80% in inflamed liver tissues at 500 μg siRNA per kg, and notably reduced serum TNF-α levels to achieve potent anti-inflammatory performance against ALF.
研究领域:
药理学
·
纳米技术
·
分子生物学
·
治疗学
✓ 已验证
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
·
2018
·
IF 3.466
Yuzhe Huang,Jian Guo,Shuangying Gui
The current treatments used in inflammatory bowel disease (IBD) therapy have significant side effects. Thus, it is very necessary to position and release TNF-α siRNA in inflamed tissues. Here, we demonstrate that poly(lactic- co -glycolic acid) can pack TNF-α siRNA efficiently into nanoparticles (NPs), and galactosylated chitosan (GC) can be grafted onto the NP surface, improving the RAW 264.7 macrophage-targeting kinetics of the NPs in vitro. Next, we orally administered GC-modified NPs loaded with TNF-α siRNA to C57BL/6 mice treated with 3% dextran sodium sulfate (DSS) to investigate their use in the treatment of colitis . When TNF-α siRNA loaded NPs were released into the colitis tissues of mice, GC-modified NPs (GPNs) alleviated the inflammation more efficiently than unmodified PGLA NPs (PNs). A series of colitis parameters (e.g., weight loss, myeloperoxidase (MPO) activity) demonstrated that GPNs have better anti-inflammatory effects than PNs. As indicated by flow cytometry, grafting GC onto NPs increased the macrophage uptake capacity and improved the kinetics of endocytosis. Collectively, our findings indicate that GC- modified TNF-α siRNA loaded NPs are powerful and efficient nanoscale materials for the delivery of therapeutic molecules to colitis tissues.
研究领域:
药学
·
生物技术
·
纳米医学
·
炎症研究
·
药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）