ACS Applied Materials & Interfaces
·
2022
·
IF 10.383
Qing Hu,Jiayi Yao,Xiaoqin Wang,Yanfang Wang,Xiaoling Fu,Ju Ma,Han Lin,Jiaqi Xu,Longhua Shen,Xiangbin Yu
Chemoimmunotherapy can synergistically enhance the therapeutic effects and decrease the side effects by a combined method. However, the effective targeted codelivery of various chemotherapeutic agents and siRNAs remains challenging. Although nanomedicine-based chemoimmunotherapy has shown great potential in cancer treatment in recent years, further effort is needed to simplify the nanocarrier designs and maintain their effective functions. Here, we report a simple but robust multifunctional liposomal nanocarrier that contains a pH-sensitive liposome (LP) shell and a dendritic core for tumor-targeted codelivery of programmed cell death ligand 1 (PD-L1) siRNA and doxorubicin (DOX) (siPD-L1@PM/DOX/LPs). siPD-L1@PM/DOX/LPs had a suitable particle size and zeta potential, excellent stability in serum, and pH-sensitive drug release in vitro. They exhibited significant cell proliferation inhibition compared to free DOX and DOX-loaded LPs and could escape endosomes, effectively release siRNA into the cytoplasm of MCF-7 cells, and significantly reduce the PD-L1 expression on tumor cells. In vivo imaging confirmed high accumulation of siPD-L1@PM/DOX/LPs at the tumor site. More importantly, compared with siPD-L1@PM/LPs or DOX alone, siPD-L1@PM/DOX/LPs were more effective in inhibiting tumor growth and activating cytotoxic T cells in vivo. In conclusion, this nanocarrier may hold promise as a codelivery nanoplatform to improve the treatment of various solid tumors.
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PubMed
高影响因子
Acta Biomaterialia
·
2021
·
IF 8.947
Ye Yuan,Jia Liu,Xiangnan Yu,Xingxin Liu,Yanni Cheng,Cheng Zhou,Mingyi Li,Lin Shi,Yan Deng,Huan Liu,Guobin Wang,Lin Wang,Zheng Wang
Multidrug resistance (MDR) is a major cause accounting for chemotherapy failure and recurrence of malignant tumors. A prominent mechanism underlying MDR is overexpression of P-glycoprotein (P-gp, a drug efflux pump). Promoting drug delivery efficacy by targeting tumor and concurrently suppressing drug efflux through down-regulating P-gp emerges as an effective strategy to enhance intracellular drug accumulation for combating MDR tumor. General Control Non-repressed 5 (GCN5), a histone acetyltransferase acting as an epigenetic regulator of multidrug resistance protein 1 (MDR1), positively regulates P-gp levels in drug-resistant cancer cells. Herein, a hyaluronic acid-coated, pH/redox dual-responsive nanosystem (HPMSNs) is fabricated for co-delivering doxorubicin (DOX) and GCN5 siRNA (siGCN5). This nanosystem can effectively encapsulate DOX and siRNA preventing premature leakage and releasing these therapeutics intracellularly via its pH/redox dual responsiveness. Through CD44-mediated targeting, DOX/ [email protected] increases drug internalization in CD44-overexpressing cancer cells, and markedly promotes DOX retention by down-regulating P-gp expression in drug-resistant cancers through silencing GCN5. Of note, in an MDR breast tumor model, DOX and siGCN5 co-delivered HPMSNs inhibits MDR tumor growth by 77%, abolishes P-gp-mediated drug resistance, and eliminates DOX's systemic toxicity. Thus, the tumor-targeting, stimuli-responsive nanosystem is an effective carrier for co-delivering anticancer drug and siRNA for combating cancer drug resistance. Statement of significance We designed a tumor-targeting, pH/redox dual-responsive nanosystem (HPMSNs) for chemo-drug and siRNA co-delivery. This nanosystem efficiently co-delivered DOX and siGCN5 into drug-resistant cancer cells and significantly inhibited the tumor growth through: (1) HA shell enhanced the cellular internalization of loaded DOX and siGCN5 via CD44-mediated targeting; (2) the pH/redox dual-responsive nanosystem released the cargos in response to the intracellular environment; (3) the released siGCN5 downregulated P-gp epigenetically. In an MDR breast tumor model (MCF7/ADR), DOX and siGCN5 loaded HPMSNs markedly inhibited tumor growth, almost completely abolished P-gp expression, and minimized systemic toxicity of DOX.
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PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2026
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IF 8.7
Junbo Jiang,Miaomiao Zhang,Yutao Zheng,Shixin Xu,Jinxin Zhang,Zhiyi Gao,Jieru Li,Bo Li,Wenting Xu,Li Xie,Wen Zhao
Dual-Crosslinking Strategy: A dual network combining genipin-mediated Schiff base dynamic bonding and Ca 2+ coordination cross-linking for mechanical reinforcement and nanoparticle anchoring. • Nucleic acid drug delivery and gene intervention: IL-11 siRNA-loaded LNPs anchored in hydrogel enable sustained release, silencing IL-11 and fibrotic genes to inhibit myofibroblast activity and remodel collagen for anti-fibrosis. • Scar-free healing promotion: SQG/si IL11 @NPs dressing reduces scar index and thickness, restores collagen I/III ratio, downregulates α-SMA and TGF-β1, enabling near scar-free skin regeneration. Hypertrophic scars often cause functional impairment and aesthetic damage, thereby affecting patients' daily life and comfort. Moreover, existing therapies have limited efficacy and are prone to recurrence. To achieve precise genetic intervention, this study constructed a time-controlled release polysaccharide hydrogel dressing for the targeted delivery of IL-11 siRNA. This dressing is based on a chitosan quaternary ammonium (QCS)/sodium alginate (SA) double-network structure hydrogel (SQG) and loaded with cationic lipid nanoparticles (si IL11 @NPs), forming an “integrated drug-loading and cross-linking” system. SQG hydrogel also shows good antibacterial activity and anti-inflammatory properties, which is helpful to establish a wound microenvironment that inhibits scar hyperplasia. It continuously releases siRNA during the mid-to-late stage of wound healing (days 5–9). Cell experiments showed that the released nanoparticles were efficiently internalized by TGF-β1-induced myofibroblasts, significantly inhibiting their migration and proliferation and downregulating the expression of IL-11 and the typical fibrotic genes COL1A1, FN1, and ACTA2. In the rabbit ear scar model, this dressing promoted wound healing, inhibited late-stage hypertrophy, reduced the scar elevation index and thickness, improved collagen alignment and the type I/III collagen ratio, and downregulated the expression of α-SMA and TGF-β1. In summary, the SQG/si IL11 @NPs hydrogel dressing shows good potential and provides a new option for inhibiting hypertrophic scar formation in wound treatment.
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PubMed
高影响因子
World Journal of Surgical Oncology
·
2026
·
IF 2.8
Wang Ju,Zhang Yong,Li Heyu,Peng Jikui,Li Haijun,Gao Xiaoping
STIL is a key molecule influencing the proliferation and cell cycle of gastric cancer cells; however, STIL is also expressed in normal tissues. Therefore, designing a drug delivery system that targets gastric cancer cells is crucial for STIL-targeted therapy. In this study, we constructed exosomes targeting the HER-2 receptor and loaded with siSTIL (Anti-HER-2-Exo-siSTIL), and validated the inhibitory effects of Anti-HER-2-Exo-siSTIL on gastric cancer proliferation and metastasis in vivo. Anti-HER-2-Exo-siSTIL was able to enter SGC-7901 cells and inhibit STIL expression, significantly suppressing the growth of SGC-7901 xenograft tumors. By downregulating STIL and the anti-apoptotic protein Bcl-2, and upregulating the pro-apoptotic proteins Bax, Caspase-3, and Caspase-9, Anti-HER-2-Exo-siSTIL effectively induced apoptosis in tumor cells. Furthermore, Anti-HER-2-Exo-siSTIL selectively inhibited lung metastasis of SGC-7901 cells via hematogenous dissemination. In summary, Anti-HER-2-Exo-siSTIL specifically targets and suppresses gastric cancer proliferation and lung metastasis, demonstrating its significant translational potential for gastric cancer therapy.
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高影响因子
MOLECULAR PHARMACEUTICS
·
2025
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IF 4.5
Zhen Zhang,Hongbo Wang,Zhijun Zhang,Yaoyao Zhang,Huajing Sun,Xi Chen,Jiayu Gu,Yanling Gong
Small interfering RNA (siRNA)-based therapy, which silences disease-associated genes, has emerged as a potential therapeutic strategy for various disorders, including cancer. Lipid nanoparticles (LNPs) have become a leading platform for efficient siRNA delivery. SOX9, a family member of SRY-related high-mobility-group box (SOX) transcription factors, plays an important role in the pathogenesis and progression of colorectal cancer (CRC). Here, we developed cRGDfK peptide-modificed LNPs (R-LNPs) composed of DLin-MC3-DMA, DMG-PEG, DSPC, DSPE-PEG-cRGDfK, and cholesterol for the targeted delivery of SOX9 siRNA (siSOX9) in CRC treatment. The formulation, delivery, and antitumor effect on CRC in vitro and in vivo were explored. The optimized R-LNPs exhibited favorable physicochemical properties including a uniform particle size (159.6 ± 0.93 nm), low polydispersity index (PDI = 0.207 ± 0.016), near-neutral zeta potential (2.74 ± 0.35 mV), and high encapsulated efficiency (90.71 ± 1.63%). Additionally, R-LNPs demonstrated sustained and controlled in vitro release and good serum stability. The prepared R-LNPs were efficiently uptaken by HCT-116 via clathrin, lipid rafts, and caveolae dependent endocytosis and macropinocytosis. Subsequently, R-LNPs were colocalized with lysosomes before escaping into the cytoplasm, ensuring effective siRNA release. In vivo distribution studies confirmed tumor-specific accumulation for R-LNPs in HCT-116 xenograft models. Functionally, R-LNPs loading siSOX9 inhibited the proliferation, migration, and invasion of HCT-116 cells and Caco-2 cells (P < 0.05 or 0.01) and inhibited tumor growth and proliferation in tumor-bearing mice (P < 0.05 or 0.01). The antitumor effects were attributed to the silence of SOX9, which subsequently downregulated key oncogenic mediators, including β-catenin, cyclin D1, and c-Myc (P < 0.05 or 0.01). Furthermore, R-LNPs demonstrated favorable safety in in vivo application. In conclusion, our cRGDfK-modified LNPs loading siSOX9 represent a promising targeted therapeutic strategy for CRC, offering both efficacy and biocompatibility.
研究领域:
药剂学
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肿瘤学
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纳米技术
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分子生物学
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药物递送
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生物技术
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PubMed
高影响因子
International Journal of Nanomedicine
·
2021
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IF 6.4
Jialang Zhuang,Siqi Chen,Ye Hu,Fan Yang,Qin Huo,Ni Xie
Introduction Metastatic breast cancer seriously harms women’s health and is currently the tumour type with the highest mortality rate in women. Recently, the combinatorial therapeutic approaches that integrate anti-cancer drugs and genetic agents is an attractive and promising strategy for the treatment of metastatic breast cancer. Moreover, such a combination strategy requires better drug carriers that can effectively deliver the cargo to the breast cancer cells and achieve controlled release in the cells to achieve better therapeutic effects. Methods The tumour-targeted and redox-responsive mesoporous silica nanoparticles (MSNs) functionalised with DNA aptamers (AS1411) as a co-delivery system was developed and investigated for the potential against metastatic breast cancer. Doxorubicin (Dox) was loaded onto the MSNs, while AS1411 and a small interfering RNA (siTIE2) were employed as gatekeepers via attachment to the MSNs with redox-sensitive disulfide bonds. Results The controlled release of Dox and siTIE2 was associated with intracellular glutathione. AS1411 mediated the targeted delivery of Dox by increasing its cellular uptake in metastatic breast cancer, ultimately resulting in a lower IC50 in MDA-MB-231 cells (human breast cancer cell line with high metastatic potency), improved biodistribution in tumour-bearing mice, and enhanced in vivo anti-tumour effects. The in vitro cell migration/invasion assay and in vivo anti-metastatic study revealed synergism in the co-delivery system that suppresses cancer cell metastasis. Conclusion The tumour-targeted and redox-responsive MSN prepared in this study are promising for the effective delivery and controlled release of Dox and siTIE2 for improved treatment of metastatic breast cancer.
研究领域:
肿瘤学
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药学
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纳米技术
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癌症治疗
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PubMed
高影响因子
Biomaterials Science
·
2023
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IF 6.6
Zixu Liu,Linxuan Zhao,Yupeng Feng,Qingqing Wang,Nan Dong,Yu Zhang,Tian Yin,Haibing He,Xing Tang,Jingxin Gou,Li Yang
Cancer vaccine-based immunotherapy has great potential; however, vaccine has been hindered by the immunosuppressive tumor microenvironment (TME). In this study, dual-responsive PEG-lipid polyester nanoparticles (PEG BR647-NP) for tumor-targeted delivery were proposed. PEG BR647-NP containing model tumor associated antigen (TAA) OVA and signal transduction and activator of transcription 3 (STAT3) siRNA were delivered to tumor. PEG BR647-NP was internalized by tumor associated dendritic cells (TADCs), where TAA and siRNA were released into cytoplasm via endo/lysosome escape effect. The released OVA was presented by the major histocompatibility complex class I to activate T cells, the released STAT3 siRNA acted to relieve TADCs dysfunction, promote TADCs maturation, improve antigen-presenting ability, and enhance anticancer T cell immunity. Meanwhile, PEG BR647-NP was ingested by tumor cells, and could kill tumor cells by the pro-apoptosis effect of STAT3 siRNA. Moreover, PEG BR647-NP could reduce the proportion of myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) in tumors and abrogate immunosuppression. The integration of relieved TADCs dysfunction, promoted TADCs maturation, enhanced antigen cross-presentation, abrogated immunosuppression, and improved pro-apoptosis effect can boost the vaccination for tumor immunotherapy. Thus, PEG BR647-NP efficiently delivered vaccine and STAT3 siRNA to tumor, and modulated immunosuppressive TME, provided better antitumor effects.
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PubMed
高影响因子
PHYTOMEDICINE
·
2025
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IF 8.3
Anna Gan,Haimiao Chen,Fei Lin,Ruixuan Wang,Bo Wu,Tingxu Yan,Ying Jia
Background Acute lung injury (ALI) is a serious respiratory ailment marked by dysregulation of the immune dysregulation and an inflammatory reaction.Currently, effective treatment options for ALI are limited. Sanzi Yangqin Decoction (SZYQ) is a traditional formula used clinically to treat respiratory diseases, although its effects on ALI have not yet been fully elucidated. Purpose This research seeks to elucidate the pharmacodynamic material basis of SZYQ within the context of lipopolysaccharide (LPS)-induced ALI, thereby establishing a robust foundation for considering SZYQ as a possible intervention for improving ALI. Methods The chemical constituents of SZYQ were identified by UHPLC-QTOF-MS. The pharmacological mechanism of SZYQ on ALI was preliminarily investigated through network pharmacology. An ALI model induced by LPS was employed to evaluate the efficacy of SZYQ via histopathological analysis and other methodologies. Transcriptomic analysis of lung tissue from ALI mice was conducted to uncover the potential mechanisms underlying SZYQ's effects. Additionally, LPS was used to induce murine alveolar macrophages (MH-S), creating an in vitro ALI model; siRNA was introduced to further validate the pharmacological mechanisms of SZYQ's protective effects on ALI. Results This study identified a total of 37 chemical components within SZYQ, and network pharmacology results indicated that these components exert their effects via the Toll-like receptor pathway. The protective effects of SZYQ on ALI are manifested by the modulation of the immune response and the reduction of lung epithelial barrier damage. Transcriptomics, western blot, flow cytometry, and siRNA experiments demonstrated that SZYQ can inhibit levels of TLR2, p-NF-κB/NF-κB, p-IκB/IκB, p-IKKα/IKKα, MyD88, NLRP3, Caspase-1 and ASC. Furthermore, SZYQ was observed to reduce the release of reactive oxygen species (ROS), suppresses inflammasome activation, as well as decrease the incidence of cell pyroptosis. Conclusions This article demonstrated for the first time that SZYQ can enhance ALI through immune regulation. The proposed mechanism of action involved the TLR2-mediated NF-κB/NLRP3 signaling pathway and the inhibition of NLRP3 inflammasome activation.
研究领域:
药理学
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免疫学
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呼吸医学
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传统中医
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PubMed
高影响因子
Nature Communications
·
2021
·Vol. 12
·期 1
·1-14
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IF 14.919
Wang Yuqin,Guan Xiaoyu,Zhang Shanyu,Liu Yao,Wang Sha,Fan Pingping,Du Xiaoyu,Yan Shuanghong,Zhang Panke,Chen Hong-Yuan,Li Wenfei,Zhang Daoqiang,Huang Shuo
Folding of RNA can produce elaborate tertiary structures, corresponding to their diverse roles in the regulation of biological activities. Direct observation of RNA structures at high resolution in their native form however remains a challenge. The large vestibule and the narrow constriction of a Mycobacterium smegmatis porin A (MspA) suggests a sensing mode called nanopore trapping/translocation, which clearly distinguishes between microRNA, small interfering RNA (siRNA), transfer RNA (tRNA) and 5 S ribosomal RNA (rRNA). To further profit from the acquired event characteristics, a custom machine learning algorithm is developed. Events from measurements with a mixture of RNA analytes can be automatically classified, reporting a general accuracy of ~93.4%. tRNAs, which possess a unique tertiary structure, report a highly distinguishable sensing feature, different from all other RNA types tested in this study. With this strategy, tRNAs from different sources are measured and a high structural conservation across different species is observed in single molecule.
研究领域:
纳米技术
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生物物理学
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生物信息学
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分子生物学
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DOI
PubMed
高影响因子
Cell Reports
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2025
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IF 6.9
Yixuan Feng,Yiming Wang,Tai Wang,Lingtong Liu
Plant-unique RNA polymerase IV (RNA Pol IV) governs the establishment of small RNA (sRNA)-directed DNA methylation (RdDM). In dicotyledon, elevated RdDM activity is often associated with embryogenesis; however, the loss of RdDM frequently results in indiscernible phenotypes. Here, we report that the absence of SlNRPD1 , encoding the largest subunit of RNA Pol IV, leads to diminished RdDM and abnormal embryogenesis in tomato ( Solanum lycopersicum ). Hypermethylation at pericentric transposable elements (TEs) and a burst of 21/22-nt siRNA from the distal and pericentric genes are observed in slnrpd1 embryos. The specific activation of endoribonuclease Dicer-like 2 ( SlDCL2b / c / d ) is correlated with 21/22-nt sRNA accumulation. Auxin and WUSCHEL-related homeobox (WOX) signaling gene expression is altered by mCHH hypomethylation, which may lead to defective embryos. Due to improper maturation, the slnrpd1 embryos cannot withstand post-harvest desiccation. This study provides insights into how DNA methylation regulates plant embryogenesis.
研究领域:
植物生物学
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表观遗传学
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分子遗传学
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DOI
PubMed
高影响因子
Acta Pharmaceutica Sinica B
·
2025
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IF 14.6
Yanyan Xu,Xiangtong Ye,Yanfeng Du,Wenqin Yang,Fan Tong,Wei Li,Qianqian Huang,Yongke Chen,Hanmei Li,Huile Gao,Weiwei Zhang
Alzheimer’s disease (AD), characterized by β -amyloid (A β ) aggregation and neuroinflammation, remains a formidable clinical challenge. Herein, we present an innovative nose-to-brain delivery platform utilizing lactoferrin (Lf)-functionalized lipid nanoparticles (LNPs) co-encapsulating α -mangostin ( α -M) and β -site APP cleaving enzyme 1 (BACE1) siRNA (siB). This dual-modal therapeutic system synergistically combines the neuroprotective and microglia-reprogramming capabilities of α -M with the transcriptional silencing of BACE1 via siB, thereby simultaneously inhibiting A β production and enhancing its clearance. Fabricated via a microfluidic approach, the LNPs exhibited uniform particle size distribution, great encapsulation efficiency, and robust colloidal stability. Upon intranasal administration, Lf-functionalization enabled superior brain-targeting efficacy through receptor-mediated transcytosis. In vitro studies demonstrated that α -M reversed A β -induced low-density lipoprotein receptor downregulation, promoting microglial phagocytosis and autophagic degradation of A β , while siB effectively suppressed BACE1 expression, abrogating A β synthesis. In vivo investigations in APP/PS1 transgenic mice revealed remarkable cognitive recovery, substantial A β plaque reduction, and alleviation of neuroinflammation and oxidative stress. This intricately designed LNP system, exploiting a non-invasive and efficient nose-to-brain delivery route, provides a biocompatible, synergistic, and transformative therapeutic strategy for the multifaceted management of AD.
研究领域:
神经科学
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药剂学
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分子生物学
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DOI
PubMed
高影响因子
Nano Today
·
2024
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IF 13.2
Jiaying Jin,Yijia Li,Feiyang Deng,Long Yang,Yuxing Lin,Canyu Yang,Wenbing Dai,Hua Zhang,Bing He,Qiang Zhang,Xueqing Wang
KRAS gene is mutated in 40 % of colorectal cancers (CRC), which induces malignant proliferation by regulating cellular nutrient metabolism and biosynthesis. It has been found that malignant proliferation of KRAS-mutant colorectal cancer relies on the upregulation of SLC25A22 protein expression, suggesting that inhibition the expression of both KRAS and SLC25A22 is a potential CRC therapeutics. Stably knocking down the oncogenic KRAS-G12V gene can achieve long-term gene therapy effects, while transient downregulation of SLC25A22, a normal functional gene most of the time, is preferred to kill tumor cells and minimize the side impact on normal cells. Here, two lipid nanoparticles (LNP) were designed to encapsulate KRAS-G12V CRISPR/Cas9 gene editing plasmids (pKRAS-LNPs) and SLC25A22 siRNA (siSLC-LNPs), respectively. Therapeutic effects of both nanoparticles alone and in combination on KRAS-G12V mutant colorectal cancer cells in vitro were first examined. The result showed that delivery of pKRAS-LNPs or siSLC-LNPs alone could effectively achieve KRAS-G12V gene editing or SLC25A22 gene silencing and inhibit tumor cell proliferation, while co-delivery of both LNPs could achieve stronger inhibition of tumor cell proliferation by inducing stronger apoptosis. Furthermore, we found that co-delivery of pKRAS-LNPs and siSLC-LNPs induced stronger apoptosis and cell proliferation inhibition compared to pKRAS&siSLC-LNPs that were constructed by pre-mixing pKRAS and siSLC and then encapsulating them. Finally, we validated that co-delivery of pKRAS-LNPs and siSLC-LNPs can achieve KRAS-G12V colorectal cancer treatment in vivo with a tumor inhibition rate of 61.15 %. In summary, the delivery vectors constructed for nucleic acids targeting KRAS and SLC25A22 achieved therapeutic targeting of KRAS-G12V colorectal cancer in vitro and in vivo .
研究领域:
肿瘤学
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分子生物学
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基因治疗
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癌症研究
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DOI
高影响因子
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