Journal of Materials Chemistry B
·
2024
·
IF 6.1
Yan Zhang,Qin LiMiao,Feng MengFan,Xianghui Yu,Yuqing Wu
Small interfering RNA (siRNA), comprising 21-23 nucleotides, functions by complementary binding to specific mRNA sequences, thereby suppressing target protein expression. Despite their vast potential in disease therapy, siRNAs face challenges due to their susceptibility to degradation and high electronegativity, rendering them unstable in the bloodstream and impeding their passage across endothelial barriers. Moreover, successful intracellular delivery necessitates overcoming endosomal entrapment, posing a significant hurdle for carrier material development. In this study, leveraging the strong affinity of histidine oligomers (His6) for metal ions, we engineered nanoparticles (HmA) by gentle assembly with divalent zinc ions under pH=8 conditions. We designed the RNA-binding functional peptide L2-NTD to enhance siRNA stability and delivery efficiency when complexed with HmA. The resulting siRNA+L2-NTD@HmA nanoparticles were formed via in situ encapsulation, ensuring efficient siRNA delivery into cells with minimal cytotoxicity and degradation. This approach presents a novel strategy for the design and artificial fabrication of carriers for effective RNA delivery.
研究领域:
分子生物学
·
药物递送
·
纳米医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nature Communications
·
2025
·Vol. 16
·期 1
·1-15
·
IF 15.7
Liu Zhen,Wu Jiacai,Wang Ning,Lin Yongqi,Song Ruiteng,Zhang Min,Li Bin
Despite remarkable progress in designing RNA delivery systems, endosomal escape remains a recognized challenge for efficient RNA delivery. In this study, we develop a robust mRNA delivery platform termed endosomolytic chloroquine-like optimized lipid nanoparticles (ecoLNPs) for versatile mRNA delivery in vitro and in vivo via integrating the signature scaffold extracted from endosomolytic chloroquine into ionizable lipids. RNase-resistant ecoLNPs are capable of delivering a broad variety of mRNA payloads to diverse cell types, even hard-to-transfect 3D cells, with an efficiency of up to 18.9-fold higher than that of commercial transfection reagents. The pH-responsive endosomolytic activity of ecoLNPs can be largely attributed to the proton sponge effect and saposin B-promoted membrane disruption. In vivo, ecoLNPs enable potent local and systemic mRNA delivery and exhibit comparable potency to the clinically approved mRNA vaccine carrier, but strong tropism for lymph nodes following intramuscular injection. Furthermore, ecoLNPs are able to retain in vivo delivery potency for at least one week under non-frozen conditions and induce efficient genome editing in transgenic mice. Overall, the structure-guided integration strategy provides a pathway for de novo design of endosomolytic mRNA delivery systems.
研究领域:
分子生物学
·
纳米医学
·
药物递送
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nanoscale
·
2017
·Vol. 10
·期 3
·1063-1071
·
IF 7.367
Huahua Yue,Xiaoming Zhou,Meng Cheng,Da Xing
Direct cellular delivery of CRISPR/Cas9 complexes is of great significance for genome editing and other recently developed applications, such as gene expression regulation and RNA/DNA imaging. Here, we first constructed a graphene oxide (GO)-polyethylene glycol (PEG)-polyethylenimine (PEI) nanocarrier for the delivery of high-molecular-weight Cas9/single-guide RNA (sgRNA) complexes for endocytosis, endosomal escape, nuclear entry, and gene editing. The results demonstrate that the nanocarrier can be used successfully for efficient gene editing in human AGS cells with an efficiency of ∼39%. The results also show that this nanocarrier can protect sgRNA from enzymatic degradation, thus exhibiting extremely high stability, which is critical for future in vivo applications. Thus, this GO-mediated Cas9/sgRNA delivery system has potential as a new approach for biomedical research and targeted gene engineering applications.
研究领域:
生物技术
·
遗传学
·
纳米医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
COLLOIDS AND SURFACES A-PHYSICOCHEMICAL AND ENGINEERING ASPECTS
·
2023
·
IF 5.2
Hailiang Chen,Chenyu Liu,Simiao Yu,Hengjun Zhou,Farishta Shafiq,Weihong Qiao
The emergence of liposomes has provided a breakthrough for the clinical use of highly toxic chemotherapeutic drugs . However, the clinical effects of conventional drug-loaded liposomes are unsatisfactory due to the lack of specific targeting of cancer cells and the inability to achieve endosome escape and controllable release in vivo. In this paper, a cRGD-PEOz-Hz-DOB (cPzD) molecule with specific targeting, endosomal escape, and endogenous acid-sensitive controlled release ability was creatively designed and synthesized to prepare drug-loaded liposomes cPzDGX encapsulating the anticancer drug Doxorubicin (DOX) in order to enhance the anticancer performance of DOX. The study found that the hydrazone bond in cPzD reached a breakage rate of 42% within 48 h at pH 5.0, so the cumulative release rate of cPzDGX at pH 5.0 for 48 h was as high as 82.9%, which was 22.5% higher than that at pH 7.4. Moreover, the uptake of cPzDGX in A549/ADR cells was increased by 62% at 2 h, and the expression of the green fluorescent protein gene EGFP was also increased by 36% relative to the targeting control group, indicating that cRGD modification could effectively improve the targeting ability of liposomes to cancer cells. In addition, it was demonstrated that PEOz modification could help drug carriers achieve endosome escape because the green fluorescent protein expression in the PEOz-modified liposome group was 60.5% higher than that in the PEG-modified group. Finally, the cell viability of the cPzDGX group decreased by 17.2% relative to the free DOX group when the DOX concentration was 1 μg/mL in the cytotoxicity assay, and the diameter reduction of 3D tumor MCs increased by 34.4%. And cPzDGX could effectively enhance the permeability of free DOX to solid tumors. The above results indicate that the DOX-loaded liposomes cPzDGX we designed have great prospects for the accurate and efficient treatment of cancer.
研究领域:
肿瘤学
·
药剂学
·
生物化学
✓ 已验证
产品关联
DOI
高影响因子
MOLECULAR PHARMACEUTICS
·
2018
·
IF 4.556
Yun Zhu,Tingting Meng,Yanan Tan,Xiqin Yang,Yupeng Liu,Xuan Liu,Fangying Yu,Lijuan Wen,Suhuan Dai,Hong Yuan,Fuqiang Hu
The critical process and step in achieving effective antitumor therapies is facilitating endosomal escape, which can enhance the intracellular target delivery of therapeutics. However, the normally adopted approaches tend to result in colloidal instability as a result of the inevitable interactions between the resulting positively charged surfaces of micelles and proteins in vivo. Herein, negatively charged surface shielded polymeric micelles, consisting of polymethylacrylamide derivatives and hydrophilic chitosan (Mw = 18.8 kDa) linked by 3,3′-dithiodipropionic, are constructed. Until the pH decreases to less than 4.5, the DOX-loaded polymeric micelles (CSO-SS-PDPA/DOX) retain a negative surface charge as a result of the abundant amide groups, which could resist formation of the protein “corona” as visualized by transmission electron microscopy. Robust endosomal escape within tens of minutes due to protonated amine groups and specific redox-responsive drug release is visualized by confocal microscopy. The superior therapeutic efficacy in both 3D tumor spheroids and MCF-7 bearing mice further suggested that the prepared CSO-SS-PDPA/DOX is a promising approach for maintaining colloidal stability while achieving intracellular endosomal/lysosomal escape, which opens new opportunities for drug delivery.
研究领域:
药剂学
·
生物医学工程
·
肿瘤学
✓ 已验证
DOI
PubMed
高影响因子
NEW JOURNAL OF CHEMISTRY
·
2016
·Vol. 40
·期 11
·9806-9812
·
IF 3.277
Zhibing Sun,Dezhong Zhou
Three oligomeric linear poly(beta-amino esters) (PAEs) were synthesized and used to improve the gene transfection efficiency and reduce the cytotoxicity of poly(L-lysine) (PLL). The synthesized PAEs can co-assemble with PLL and plasmid DNA to form PLL/PAE/DNA ternary complexes of nanoscale sizes and moderate surface charges. The existence of multiple tertiary amines on PAE backbones imparts the ternary complexes with strong proton buffering capacity and therefore enhances the endosomal escape ability of the ternary complexes. In HeLa cells, the PLL/PAE/DNA ternary complexes show up to 476-fold enhancement in gene transfection efficiency when compared with the PLL/DNA binary complexes. Meanwhile, the incorporation of PAE oligomers significantly reduced the cytotoxicity of PLL. The strategy proposed here may provide insights into the development of PLL based gene delivery systems.
研究领域:
生物化学
·
分子生物学
·
基因治疗
✓ 已验证
产品关联
DOI
高影响因子
LANGMUIR
·
2023
·
IF 3.9
Hailiang Chen,Chenyu Liu,Simiao Yu,Hengjun Zhou,Farishta Shafiq,Weihong Qiao
The resistance of cancer cells to anticancer drugs has been recognized as one of the main reasons for chemotherapy failure. Multidrug combination therapy is one of the most effective ways to solve this problem. Therefore, in this article, we designed and synthesized a pH/GSH dual-responsive camptothecin/doxorubicin (CPT/DOX) dual pro-drug synergistic treatment system with the aim of overcoming the resistance of non-small cell lung cancer A549/ADR cells to DOX. The pro-drug cRGD-PEOz-S-S-CPT (cPzT) was obtained by linking CPT to poly(2-ethyl-2-oxazoline) (PEOz) with endosomal escape properties through a GSH-responsive disulfide bond and modifying it with the targeted peptide cRGD. The pro-drug mPEG–NH–N=C-DOX (mPX) was synthesized by attaching DOX to polyethylene glycol (PEG) through acid-sensitive hydrazone bonds. The dual pro-drug micelles cPzT/mPX configured according to the CPT/DOX mass ratio of 3:1 showed a strong synergistic therapeutic effect at IC50 with a combined therapy index CI = 0.49, far less than 1. Moreover, with the further improvement of the inhibition rate, the 3:1 ratio showed a stronger synergistic therapeutic effect than other ratios. The cPzT/mPX micelles not only had better targeted uptake ability but also showed a better therapeutic effect in both 2D and 3D tumor suppression assays relative to free CPT/DOX and significantly enhanced the penetration ability into solid tumors. In addition, the results of confocal laser scanning microscopy (CLSM) showed that cPzT/mPX could effectively overcome the resistance of A549/ADR cells to DOX by delivering DOX into the nucleus to exert its effect. Thus, this dual pro-drug synergistic therapy system combining targeting and endosomal escape ability provides a possible strategy to overcome tumor drug resistance.
研究领域:
药学
·
肿瘤学
·
纳米医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMACROMOLECULES
·
2014
·
IF 5.788
Qiuming Liu,Jing Chen,Jianzhong Du
The efficient intracellular drug delivery is an important challenge due to the slow endocytosis and inefficient drug release of traditional delivery vehicles such as symmetrical polymer vesicles, which have the same coronas on both sides of the membrane. Presented in this paper is a noncytotoxic poly(ethylene oxide)-block-poly(caprolactone)-block-poly(acrylic acid) (PEO113-b-PCL132-b-PAA15) triblock copolymer vesicle with an asymmetrical structure. The biocompatible exterior PEO coronas are designed for stealthy drug delivery; The pH-responsive interior PAA chains are designed for rapid endosomal escape and enhanced drug loading efficiency. The hydrophobic PCL vesicle membrane is for biodegradation. Such asymmetrical polymer vesicle showed high doxorubicin (DOX) loading efficiency and good biodegradability under extracellular enzymatic conditions. Compared with three traditional symmetrical vesicles prepared from PEO113-b-PCL110, PEO43-b-PCL98-b-PAA25, and PAA21-b-PCL75 copolymers, the DOX-loaded asymmetrical PEO113-b-PCL132-b-PAA15 polymer vesicles exhibited rapid endocytosis rate and much faster endosomal escape ability, demonstrating promising potential applications in nanomedicine.
研究领域:
生物医学工程
·
纳米医学
·
药剂学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Science Advances
·
2020
·Vol. 6
·期 33
·
IF 13.117
Guangyu Rong,Changping Wang,Lijie Chen,Yang Yan,Yiyun Cheng
Cytosolic delivery of peptides remains a challenging task owing to their susceptibility to enzymatic degradation and the existence of multiple intracellular barriers. Here, we report a new strategy to address these issues by decoration of a fluorous tag on the terminal of cargo peptides. The fluorous-tagged peptides were assembled into nanostructures, efficiently internalized by cells via several endocytic pathways and released into the cytosol after endosomal escape. They were relatively stable against enzymatic degradation and showed much higher efficiency than nonfluorinated analogs and cell penetrant peptide–conjugated ones. The proposed strategy also efficiently delivered a proapoptotic peptide into specific sites in the cells and restored the function of cargo peptide after cytosolic delivery. The fluorous-tagged proapoptotic peptide efficiently inhibited tumor growth in vivo. This study provides an efficient fluorination strategy to promote the cytosolic delivery of peptides.
研究领域:
药学
·
生物化学
·
细胞生物学
·
生物技术
·
药物化学
✓ 已验证
DOI
高影响因子
ACS Applied Nano Materials
·
2024
·
IF 5.3
Meng-Fan Feng,Li-Miao Qin,Bo Sun,Xianghui Yu,Yuqing Wu
Circular RNA (circRNA) has emerged as a promising class of therapeutics and mRNA vaccines. While possessing greater stability and functionality akin to linear mRNA, circRNA still necessitates an efficient and adaptable delivery system to surmount the primary challenge of cellular uptake and membrane penetration. Inspired by the high invasiveness of the virus, in this study, the virus-like nanoparticles (VLNPs) of human papillomavirus (HPV) have been constructed as robust carriers for circRNA encapsulation and transfer through their coassembly monitoring. Notably, the functionalization of a transmembrane peptide (L17E) on the outer surface of VLNPs has led to the development of a more efficient nanocarrier, which has significantly enhanced both the transmembrane delivery and endosomal escape of circRNA. Validation studies employing VLNPs-L17E-packaged circRNA across various cell types have demonstrated notable improvements in target protein expression, ranging from 1.48- to 2.04-fold. These findings underscore the potential of HPV-VLNPs-L17E as a carrier for circRNA delivery, offering promising prospects for RNA therapy applications in the future.
研究领域:
分子生物学
·
纳米医学
·
治疗递送系统
·
基因工程
✓ 已验证
产品关联
DOI
高影响因子
Nanoscale
·
2015
·Vol. 7
·期 18
·8476-8484
·
IF 7.394
Wenyu Li,Yajie Liu,Jianwei Du,Kefeng Ren,Youxiang Wang
Cell-penetrating peptides (CPP) have been widely developed as a strategy to enhance cell penetrating ability and transfection. In this work, octa-arginine modified dextran gene vector with pH-sensitivity was developed via host–guest interactions. α-Cyclodextrin was modified with octa-arginine (CDR), which had excellent cell penetrating ability. Dextran was selected as a backbone and modified with azobenzene as guest units by acid–labile imine bonds (Az-I-Dex). The supramolecular polymer CDR/Az-I-Dex with high a C/A molar ratio (molar ratio of CD on CDR to Az on Az-I-Dex) was unfavorable for DNA condensation. The dextran shell of CDR/Az-I-Dex/DNA polyplexes improved the stability under physiological conditions. However, once treated with acetate buffer (pH 5.4) for 3 h, large aggregates formed rapidly due to the cleavage of the dextran shell. As expected, the vector had cell viability of 80% even when the CDR concentration increased to 100 μg mL−1. Moreover, due to the effective cellular uptake efficiency, CDR/Az-I-Dex/DNA polyplexes had 6–300 times higher transfection efficiency than CDR/DNA polyplexes. It was even higher than high molecular weight PLL-based polyplexes of HEK293 T cells. Importantly, chloroquine as an endosomal escape agent could not improve the transfection of CDR/Az-I-Dex/DNA polyplexes, which indicated that the CDR/Az-I-Dex supramolecular polymer had its own ability for endosomal escape. These results suggested that the CPP-based polyplexes shelled with polysaccharide can be promising non-viral gene delivery carriers.
研究领域:
药学科学
·
分子生物学
·
基因治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
IET Nanobiotechnology
·
2023
·
IF 2.3
Xiu Han,Yan Lu,Zhaoluo Xu,Yanan Chu,Xueping Ma,Haiping Wu,Bingjie Zou,Guohua Zhou
Currently, organic solvents are necessary for the preparation of anionic liposomes for siRNA delivery. The removal of organic solvent is time-consuming and the residual organic solvent is not only a hidden danger, but also affects the stability of anionic liposomes. Glycerol, which is physiologically compatible and does not need to be removed, is used to promote the dispersion of lipids and the formation of anionic liposomes. Additionally, the preparation process is simple and not time-consuming. The results showed that anionic liposomes, which were typically spherical with a particle size of 188.9 nm were successfully prepared with glycerol. And with the help of Ca 2+ , siRNA was encapsulated in anionic liposomes. The highest encapsulation efficiency at 2.4 mM Ca 2+ reached 91%. And the formation of calcium phosphate could promote the endosomal escape of siRNA effectively. The results from cell viability showed that the anionic liposomes had no obvious cytotoxicity. It was also verified that anionic liposomes could improve the resistance of siRNA against degradation. Additionally, siRNA delivered by anionic liposomes could play an effective role in knockout. Therefore, anionic liposomes prepared with glycerol will be a safe and effective delivery platform for siRNA and even other nucleic acid drugs.
研究领域:
药剂学
·
纳米技术
·
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
危险品化学品经营许可证（带存储）