ANALYTICAL AND BIOANALYTICAL CHEMISTRY
·
2021
·Vol. 413
·期 13
·3493-3499
·
IF 4.157
Cao Xiuping,Shang Xinxin,Guo Yingshu,Zheng Xiaofei,Li Wenxin,Wu Di,Sun Li,Mu Shanliang,Guo Chuanen
In the process of drug carrier design, lysosome degradation in cells is often neglected, which makes a considerable number of drugs not play a role. Here, we have constructed a tumor treatment platform (Apn/siRNA/NLS/HA/Apt) with unique lysosomal escape function and excellent cancer treatment effect. Apoferritin (Apn) has attracted more and more attention because of its high uniformity, modifiability, and controllability. Meanwhile, its endogenous nature can avoid the risk of immune response being eliminated. We used aptamer modified iron deficient protein nanocages (Apn) to tightly encapsulate the combination of siRNA and NLS (siRNA/NLS) with influenza virus hemagglutinin (HA peptide). After Apn/siRNA/NLS/HA/Apt was targeted into cells, the acidic environment of lysosome led to the cleavage of Apn nanocages, and the release of siRNA/NLS and HA peptide. HA peptide can destroy lysosome membrane, make siRNA/NLS escape lysosome, and enter the nucleus under the action of NLS, resulting in efficient gene silencing effect. This kind of cancer treatment strategy based on Apn nanocage shows high biocompatibility and unique lysosome escape property, which significantly improves the drug delivery and treatment efficiency. Graphical abstract
Lysosomal escape protein nanocarriers for nuclear-targeted siRNA delivery
研究领域:
纳米医学
·
癌症生物学
·
药物递送系统
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
TECHNOLOGY AND HEALTH CARE
·
2016
·
IF 0.678
Zhang Yujuan,Song Na,Fu Jiamin,Liu Yanling,Yu Yanrong,Shi Qiaofa,Fu Yingyuan,Zhou Nanjing,Yuan Keng,Zhao Lin,Zhang Quan,Min Weiping
RNA interference (RNAi) employs double-stranded RNA or
siRNA (small interfering RNA) to silence gene expression in cells. The
widespread use of RNAi therapeutics requires the development of clinically
suitable, safe and effective delivery vehicles. PEI (Poly(ethylene imine))
carrying the positive charges has attracted considerable attention for siRNA
delivery. Gold nanorods (GNRs) exhibit specially localized surface plasmon
resonance when excited by the visible and near-infrared laser, which is
useful for photothermal therapy. However, the toxicity derived from a large
amount of the surfactant cetyltrimethylammonium bromide (CTAB) during GNR
synthesis severely limits their medical applications. Here, we report the
synthesis of GNRs-PEI/GNRs-PEI-folate to improve biocompatibility, siRNA
delivery and photothermal therapy of GNRs. Firstly, GNRs were synthesized
according to the seed-mediated template-assisted protocol. The
characterization results of GNRs showed: the size was length about 218 nm
and width about 26.8 nm; the Zeta potential was +38.1 mV derived from CTAB
on their surface; the dipole resonance extinction spectrum peak was 752 nm
which is effective for photothermal therapy in vivo. Secondly, we
synthesized PEI-MUA (Mercaptoundecanoic acid) and PEI-MUA-folate based on
the chemical reaction between amino group of PEI and carboxyl group of MUA
or Folate. PEI-MUA or PEI-MUA-folate to replace CTAB on GNRs obtained the
GNRs-MUA-PEI system or the GNRs-MUA-PEI-folate system due to the solid
conjugation between the thiol group of MUA and GNRs. The products were
measured using the FTIR Spectrometer, and the spectra suggest MUA-PEI or
PEI-MUA-folate has successfully replaced CTAB on the surface of GNRs.
Finally, GNRs-MUA-PEI was incubated with siRNA-Cy3. The unbound siRNA-Cy3
was measured the intensity of fluorescence for calculating the uploaded
amount of siRNA by GNRs-MUA-PEI, and the results indicate that the uploaded
percentage of siRNA is about 70%. We conclude that the GNRs-MUA-PEI
system is an effective siRNA loading vehicle.
研究领域:
纳米医学
·
基因治疗
·
药物递送系统
✓ 已验证
DOI
PubMed
高影响因子
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
JOURNAL OF CONTROLLED RELEASE
·
2024
·
IF 10.5
Hao Zhang,Wenjing Yan,Jinhui Wang,Shuqian Xie,W. Andy Tao,Chien-Wei Lee,Xing Zhang,Guiyuan Zhang,Yufeng Liu,Dong Wei,Jing Hu,Haohan Liu,Fengying Liu,Yamei Nie,Xue Chen,Hongtao Xu,Jiang Xia,Shizhi Wang
Osteoarthritis (OA) is the most prevalent degenerative cartilage disease, but no effective treatment is currently available to ameliorate the dysregulation of cartilage catabolism. Cartilage degeneration is closely related to the change in the physiology of chondrocytes: for example, chondrocytes of the OA patients overexpress matrix metallopeptidase 13 (MMP13), a.k.a. collagenase 3, which damages the extracellular matrix (ECM) of the cartilage and deteriorate the disease progression. Inhibiting MMP13 has shown to be beneficial for OA treatments, but delivering therapeutics to the chondrocytes embedded in the dense cartilage is a challenge. Here, we engineered the exosome surface with the cartilage affinity peptide (CAP) through lipid insertion to give chondrocyte-targeting exosomes, CAP-Exo, which was then loaded with siRNA against MMP13 (siMMP13) in the interior to give CAP-Exo/siMMP13. Intra-articular administration of CAP-Exo/siMMP13 reduced the MMP13 level and increased collagen COL2A1 and proteoglycan in cartilage in a rat model of anterior cruciate ligament transection (ACLT)-induced OA. Proteomic analysis showed that CAP-Exo/siMMP13 treatment restored the altered protein levels in the IL-1β-treated chondrocytes. Taken together, a facile exosome engineering method enabled targeted delivery of siRNA to chondrocytes and chondrocyte-specific silencing of MMP13 to attenuate cartilage degeneration.
研究领域:
医学
·
分子生物学
·
再生医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Materials Chemistry B
·
2024
·Vol. 12
·期 26
·6442-6451
·
IF 6.1
Jia-Hao Bai,Qing-Tao Yu,Yi-Wu Wang,Chun-Fa Chen,Lian-Ju Ma,Yue Yuan,Yong-Jun Gan,Jia-Qi Yang,Shu Zhu,Yu-Hang Ran,Li-Lei Zhang,Hang Qian,Zheng-Huan Zhao,Qian Liu
Self-assembled DNA nanostructures hold great promise in biosensing, drug delivery and nanomedicine. Nevertheless, challenges like instability and inefficiency in cellular uptake of DNA nanostructures under physiological conditions limit their practical use. To tackle these obstacles, this study proposes a novel approach that integrates the cationic polymer polyethyleneimine (PEI) with DNA self-assembly. The hypothesis is that the positively charged linear PEI can facilitate the self-assembly of DNA nanostructures, safeguard them against harsh conditions and impart them with the cellular penetration characteristic of PEI. As a demonstration, a DNA nanotube (PNT) was successfully synthesized through PEI mediation, and it exhibited significantly enhanced stability and cellular uptake efficiency compared to conventional Mg2+-assembled DNA nanotubes. The internalization mechanism was further found to be both clathrin-mediated and caveolin-mediated endocytosis, influenced by both PEI and DNA. To showcase the applicability of this hybrid nanostructure for biomedical settings, the KRAS siRNA-loaded PNT was efficiently delivered into lung adenocarcinoma cells, leading to excellent anticancer effects in vitro. These findings suggest that the PEI-mediated DNA assembly could become a valuable tool for future biomedical applications.
研究领域:
纳米医学
·
癌症治疗
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
Journal of Materials Chemistry B
·
2019
·Vol. 7
·期 44
·6994-7005
·
IF 5.047
Pengchong Wang,Yan Yan,Ying Sun,Rui Zhang,Chuanchuan Huo,Lu Li,Ke Wang,Yalin Dong,Jianfeng Xing
The transgelin-2 (TAGLN2) protein plays an important role in multidrug resistance in human breast cancer. siRNA mediated gene silencing of TAGLN2 is a promising strategy for paclitaxel resistance reversal in breast cancer. In this study, a series of bioreducible and acid-labile polydiethylenetriamines (PDs) with different proportions of cross-linkers were synthesized. TAGLN2 siRNA was condensed by PDs to form dual-responsive nanocomplexes, and these nanocomplexes were hypothesized to partially degrade in the acidic environment of endosomes, and then completely degrade in the reducing environment of the cytoplasm to release siRNA. It was found that PDs have good water solubility, acid–base buffering capacity, suitable degradability and high biocompatibility. Moreover, PDCKM can deliver TAGLN2 siRNA into MCF-7/PTX cells and inhibit the expression of TAGLN2 even better than PEI 25k. Besides, paclitaxel showed higher cytotoxicity in cells incubated with PDCKM/TAGLN2 siRNA nanocomplexes. These results suggested that PDs have great potential for safe and efficient siRNA delivery to reverse paclitaxel resistance in breast cancer.
研究领域:
生物化学
·
肿瘤学
·
药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
EUROPEAN POLYMER JOURNAL
·
2025
·
IF 6.3
Liangliang Chen,Siyuan Chen,Zhanbo Yi,Xianjiang Wu,Shuwen Zhong,Leiqiang Mao,Zesheng Wang,Qi Shuai,Xin Li
Cationic polymers like polyethyleneimine (PEI) are widely used for siRNA delivery, but their high positive charge density often compromises biocompatibility and in vivo stability. Balancing effective siRNA binding with reduced cytotoxicity remains a critical challenge for clinical translation. Here, we report a dual-functional modification strategy for PEI using oligosaccharides (maltose/maltotriose) and hydrophobic n-octanal to mitigate excessive cationic charge, enhance stability, and improve delivery efficiency. By synthesizing oligosaccharide-modified PEIs (OM-PEIs) and hydrophobically modified OM-PEIs (H-OM-PEIs), we identified PEI 25k -based derivatives (HC4 and HD4) as top performers, achieving complete siRNA loading at a low polymer:siRNA mass ratio (4:1, wt/wt) while exhibiting 50 % reduced protein adsorption and superior siRNA protection compared to unmodified PEI 25k . The hydrophobic modification enabled H-OM-PEIs to form compact nanoparticles with enhanced cellular uptake, leading to robust luciferase silencing in HeLa cells (2.5-fold improvement over PEI 25k ). Notably, in vivo studies revealed significant liver accumulation alongside detectable tumor delivery. This study demonstrated that combining oligosaccharide and alkyl modifications of PEI can reduce surface charge and protein adsorption while maintain high siRNA delivery efficiency, thereby mitigating the inherent toxicity of PEI and enhancing nanoparticle stability, which contributes to the advancement of PEI-based delivery systems in practical applications.
研究领域:
分子生物学
·
纳米医学
·
药物递送系统
✓ 已验证
产品关联
DOI
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2013
·
IF 3.458
Gaoyang Guo,Li Zhou,Zhifei Chen,Weilin Chi,Xiuqun Yang,Wei Wang,Biliang Zhang
Small interfering RNA (siRNA) has tremendous potential as a therapeutic agent for diverse diseases; however, due to its susceptibility to degradation and poor cellular uptake, the low efficiency of administration has been the most important limiting factor for clinical applications of siRNA. Herein, we synthesized alkyl chain modified low-molecular-weight polyethylenimines (LMW PEIs) and found that hydrophobically modified PEIs displayed enhanced efficiency in siRNA-mediated knockdown of target genes. To elucidate the mechanism for increased delivery, we characterized the polymers’ physicochemical properties and bioactivity via nuclear magnetic resonance (NMR), gel retardation assay, dynamic laser scattering (DLS) analysis, confocal laser scanning microscopy and flow cytometry. The hydrophobic modification reduced siRNA binding affinity but facilitated the formation of nanoparticles in contrast to the original PEI. The PEIs with eight and thirteen alkyl tails were able to self-assemble into nanoparticles and yielded higher cellular uptake, which leaded to even similar efficiencies of 80–90% knockdown as Lipofectamine™ 2000 control. These results suggested that the status of polymers in aqueous solution, which depended on the degree of hydrophobic modification, played an important role in the uptake of siRNA. Therefore, we provided new information on the role of hydrophobic content in the enhanced gene silencing activity.
研究领域:
分子生物学
·
基因治疗
·
药物递送系统
✓ 已验证
DOI
PubMed
高影响因子
Nature Communications
·
2025
·Vol. 16
·期 1
·1-20
·
IF 15.7
Cui Lele,Cui Yongsheng,Liu Jing,Li Wei,Wu Mengdan,Wei Xiawei,Lai Ying,Mi Peng
A major obstacle in knocking down oncogenes for tumor therapy is the efficient delivery of siRNA into the cytosolic spaces of cancer cells. Here, we genetically bioengineer biomimetic nanovesicles with tumor-recognition and enzyme-controlled membrane fusion functions for efficiently delivering small interfering RNA into cancer cells towards gene silencing tumor therapy. The siRNA@eS-BNVs are formulated by encapsulating siRNA inside the core and coating with genetically engineered HEK293T ACE2- cell membranes encoded with functional S protein, which can recognize cancer cells and initiate membrane fusion when triggered by the enzyme. The siRNA@eS-BNVs demonstrate better efficacy for cytosolic siRNA delivery and RNA interference than conventional formulations. By intravenous injection, siRNA@eS-BNVs are highly accumulated in tumors and potently inhibited tumor and lung metastasis by simultaneously silencing the epidermal growth factor receptor gene in vivo. The cancer cell-targeting and enzyme-activatable nanovesicles provide a valuable strategy for effective and precise drug delivery.
研究领域:
生物工程
·
肿瘤学
·
分子生物学
·
药剂学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMACROMOLECULES
·
2024
·
IF 5.5
Qingming Bao,Mingming Bao,Hai Xiao,Tsogzolmaa Ganbold,Shuqin Han,Huricha Baigude
The simultaneous delivery of CpG oligonucleotide along with short interfering RNA (siRNA) has the potential to significantly boost the anticancer impact of siRNA medications. Our previous research demonstrated that Curdlan nanoparticles functionalized with adenosine are capable of selectively delivering therapeutic siRNA to cancerous cells through endocytosis mediated by adenosine receptors. Herein, we synthesized a dual-ligand-functionalized Curdlan polymer (denoted by CuMAN) to simultaneously target tumor cells and tumor-associated macrophages (TAMs). CuMAN nanoparticles containing CpG and siRNA demonstrated enhanced uptake by B16F10 tumor cells and bone marrow-derived macrophages, which are facilitated by AR on tumor cells and mannose receptor on macrophages. This led to increased release of pro-inflammatory cytokines in both in vitro and in vivo settings. The synergistic effect of CpG on TAMs and RNAi on tumor cells mediated by the CuMAN nanoparticle not only suppressed the tumor growth but also strongly inhibited the lung metastasis. Our findings indicate that the CuMAN nanoparticle has potential as an effective dual-targeting delivery system for nucleic acid therapeutics.
研究领域:
生物医学工程
·
肿瘤免疫学
·
药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Pharmaceutics
·
2021
·Vol. 13
·期 9
·1428
·
IF 6.321
Dandan Luo,Xiaochun Xu,M. Zubair Iqbal,Qingwei Zhao,Ruibo Zhao,Jabeen Farheen,Quan Zhang,Peiliang Zhang,Xiangdong Kong
Pancreatic carcinoma (PC) is greatly induced by theKRASgene mutation, but effective targeted delivery for gene therapy has not existed. Small interfering ribonucleic acid (siRNA) serves as an advanced therapeutic modality and holds great promise for cancer treatment. However, the development of a non-toxic and high-efficiency carrier system to accurately deliver siRNA into cells for siRNA-targeted gene silencing is still a prodigious challenge. Herein, polyethylenimine (PEI)-modified hydroxyapatite (HAp) nanoparticles (HAp-PEI) were fabricated. The siRNA of theKRASgene (siKras) was loaded onto the surface of HAp-PEI via electrostatic interaction between siRNA and PEI to design the functionalized HAp-PEI nanoparticle (HAp-PEI/siKras). The HAp-PEI/siKras was internalized into the human PC cells PANC-1 to achieve the maximum transfection efficiency for active tumor targeting. HAp-PEI/siKras effectively knocked down the expression of theKRASgene and downregulated the expression of the Kras protein in vitro. Furthermore, the treatment with HAp-PEI/siKras resulted in greater anti-PC cells’ (PANC-1, BXPC-3, and CFPAC-1) efficacy in vitro. Additionally, the HAp-PEI exhibited no obvious in vitro cytotoxicity in normal pancreatic HPDE6-C7 cells. These findings provided a promising alternative for the therapeutic route of siRNA-targeted gene engineering for anti-pancreatic cancer therapy.Keywords:hydroxyapatite;siRNA delivery;pancreatic cancer cells;KRASgene;gene silence;anticancer
研究领域:
纳米技术
·
癌症生物学
·
基因治疗
·
药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF COLLOID AND INTERFACE SCIENCE
·
2023
·
IF 9.9
Mengru Cai,Yu Yao,Dongge Yin,Rongyue Zhu,Tingting Fu,Jiahui Kong,Kaixin Wang,Jing Liu,Aina Yao,Yidan Ruan,Wenjuan Shi,Qian Zhu,Jian Ni,Xingbin Yin
In recent years, small interfering RNA (siRNA) has been widely used in the treatment of human diseases, especially tumors, and has shown great appeal. However, the clinical application of siRNA faces several challenges. Insufficient efficacy, poor bioavailability, poor stability, and lack of responsiveness to a single therapy are the main problems affecting tumor therapy. Here, we designed a cell-penetrating peptide (CPP)-modified metal organic framework nanoplatform (named [email protected] @survivin [email protected] , [email protected] ) for targeted co-delivery of oridonin (ORI), a natural anti-tumor active ingredient) and survivin siRNA in vivo. This can improve the stability and bioavailability of siRNA and the efficacy of siRNA monotherapy. The high drug-loading capacity and pH-sensitive properties of zeolite imidazolides endowed the [email protected] with lysosomal escape abilities. The Polyethylene glycol (PEG)-conjugated CPP (PEG-CPP33) coating significantly improved the uptake in the [email protected] in vitro and in vivo. The results showed that the co-delivery of ORI and survivin siRNA greatly enhanced the anti-tumor effect of [email protected] , demonstrating the synergistic effect between ORI and survivin siRNA. In summary, the novel targeted nanobiological platform loaded with ORI and survivin siRNA presented herein showed great advantages in cancer therapy, and provides an attractive strategy for the synergistic application of chemotherapy and gene therapy.
研究领域:
纳米技术
·
药学
·
癌症研究
·
分子生物学
✓ 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）