CARCINOGENESIS
·
2024
·
IF 3.3
Chen Fangquan,Tang Hu,Lin Junhao,Xiang Limin,Lu Yanjiao,Kang Rui,Tang Daolin,Liu Jiao
Alkaliptosis, a form of regulated cell death, is characterized by lysosomal dysfunction and intracellular pH alkalinization. The pharmacological induction of alkaliptosis using the small molecule compound JTC801 has emerged as a promising anticancer strategy in various types of cancers, particularly pancreatic ductal adenocarcinoma (PDAC). In this study, we investigate a novel mechanism by which macropinocytosis, an endocytic process involving the uptake of extracellular material, promotes resistance to alkaliptosis in human PDAC cells. Through lipid metabolomics analysis and functional studies, we demonstrate that the inhibition of alkaliptosis by fatty acids, such as oleic acid, is not dependent on endogenous synthetic pathways but rather on exogenous uptake facilitated by macropinocytosis. Consequently, targeting macropinocytosis through pharmacological approaches (e.g., using EIPA or EHoP-016) or genetic interventions (e.g., RAC1 knockdown) effectively enhances JTC801-induced alkaliptosis in human PDAC cells. These findings provide compelling evidence that the modulation of macropinocytosis can increase the sensitivity of cancer cells to alkaliptosis inducers.
研究领域:
癌症生物学
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细胞生物学
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药理学
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代谢组学
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PubMed
高影响因子
Advanced Science
·
2024
·
IF 14.3
Xiao-Lin Hou,Bin Zhang,Kai Cheng,Fang Zhang,Xiao-Ting Xie,Wei Chen,Lin-Fang Tan,Jin-Xuan Fan,Bo Liu,Qiu-Ran Xu
Customizable and number-tunable enzyme delivery nanocarriers will be useful in tumor therapy. Herein, a phage vehicle, T4-Lox-DNA-Fe (TLDF), which adeptly modulates enzyme numbers using phage display technology to remodel the tumor microenvironment (TME) is presented. Regarding the demand for lactic acid in tumors, each phage is engineered to display 720 lactate oxidase (Lox), contributing to the depletion of lactic acid to restructure the tumor's energy metabolism. The phage vehicle incorporated dextran iron (Fe) with Fenton reaction capabilities. H 2 O 2 is generated through the Lox catalytic reaction, amplifying the H 2 O 2 supply for dextran iron-based chemodynamic therapy (CDT). Drawing inspiration from the erythropoietin (EPO) biosynthetic process, an EPO enhancer is constructed to impart the EPO-Keap1 plasmid (DNA) with tumor hypoxia-activated functionality, disrupting the redox homeostasis of the TME. Lox consumes local oxygen, and positive feedback between the Lox and the plasmid promotes the expression of kelch ECH Associated Protein 1 (Keap1). Consequently, the downregulation of the antioxidant transcription factor Nrf2, in synergy with CDT, amplifies the oxidative killing effect, leading to tumor suppression of up to 78%. This study seamlessly integrates adaptable T4 phage vehicles with bio-intelligent plasmids, presenting a promising approach for tumor therapy.
研究领域:
生物医学工程
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癌症治疗
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分子生物学
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纳米技术
·
酶学
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DOI
PubMed
高影响因子
TALANTA
·
2025
·
IF 6.1
Jingbo Sun,Liushunhao Chen,Hongchen Li,Chen Xu,Dong Xu,Jiali Ren
Biological staining is essential for imaging, functional investigation, and disease diagnostics. In this research, innovative green-emissive carbon dots (G-CDs) were hydrothermally prepared from 1,2,4-triaminobenzene and ascorbic acid (AA) and further explored for versatile imaging of mammalian cells, plant cells, and microorganisms. The G-CDs, exhibiting fluorescence enhancement, outperform conventional dyes in terms of staining efficiency and specificity across various biological systems. For mammalian cells (SH-SY5Y, Hep3B, and HEK293), the G-CDs can stain both the nuclei and nucleoli in 10 min via a micropinocytic endocytosis approach, with the latter brighter. Fluorescence enhancement was greater for RNA than for DNA. Interestingly, for plant cells, only cell walls were stained, because positive charges on G-CDs enable strong adsorption onto the negatively charged cell walls, thereby hindering their further entry. G-CDs can stain cell walls and nuclei for fungi (including Aspergillus flavus and Aspergillus niger ), and cell walls and nucleoids for bacteria ( Bacillus subtilis and Escherichia coli ). The targeted staining arises from both the binding of G-CDs to DNA, RNA, pectin, peptidoglycan, and cellulose, and fluorescence enhancement due to surface passivation inhibiting rotation and vibration of functional groups. Electrostatic interactions, coordination, hydrogen bonding, and amidation collectively account for the interactions between G-CDs and these biomolecules . Finally, their practical applications in leucorrhea examinations demonstrated their capability to differentiate between bacterial and fungal vaginosis, highlighting their potential in clinical diagnostics.
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高影响因子
ACS Nano
·
2025
·
IF 16
Yushuang Wei,Haibo Chen,Rong Xu,Zhenyu Zhang,Xiangyang Li,Cheng Xu,Hongbo Pang,Kai Yang,Bing Yuan
The rational design of multicomponent nanocarriers for synergistic drug delivery remains a central goal of nanomedicine, yet progress is often hindered by an incomplete understanding of the underlying biophysical principles. Here, we investigate the role of nanoparticle shape in ″bystander uptake″, a process where the active cellular uptake of functionalized nanoparticles (F-NPs) promotes the co-internalization of nonfunctionalized bystander nanoparticles (B-NPs). Combining experiments, simulations, and theory, we demonstrate a nonmonotonic dependence on B-NP geometry, with nanorods of aspect ratio (AR) ≈ 3 exhibiting markedly superior uptake compared to other shapes including the spherical, triangular, or plate-like counterparts. Molecular dynamics simulations reveal that this enhancement stems not from greater binding affinity but from shape-dependent entropic force that drives rapid particle reorientation, which is linked to metastable trapping in a ″staircase″ free energy landscape. Crucially, this experimentally observed optimal AR cannot be explained by single-particle models but is successfully predicted by our theoretical framework incorporating the collective action of F-NPs. This model identifies AR ≈ 3 as a ″sweet spot″ that balances entropic advantages against rotational constraints. These findings establish shape selectivity as a principle for multicomponent nanocarrier design, shifting the focus from optimizing enthalpy-modulated end-state affinity to engineering entropy-driven state transitions.
研究领域:
纳米医学
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生物物理学
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药物递送
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纳米材料
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细胞生物力学
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DOI
PubMed
高影响因子
ACS Nano
·
2024
·
IF 15.8
Dan Yuan,Zhicheng Niu,Wenyu Zheng,Qiangzhong Zhao,Feibai Zhou,Mouming Zhao
Overcoming intestinal epithelial barriers to enhance bioavailability is a major challenge for oral delivery systems. Desirable nanocarriers should simultaneously exhibit rapid mucus penetration and efficient epithelial uptake; however, they two generally require contradictory structural properties. Herein, we proposed a strategy to construct multiperformance nanoparticles by modifying the rigidity of amphiphilic nanostructures originating from soy polypeptides (SPNPs), where its ability to overcome multibarriers was examined from both in vitro and in vivo, using curcumin (CUR) as a model cargo. Low-rigidity SPNPs showed higher affinity to mucin and were prone to getting stuck in the mucus layer. When they reached epithelial cells, they tended to be endocytosed through the clathrin and macropinocytosis pathways and further transferred to lysosomes, showing severe degradation and lower transport of CUR. Increased particle rigidity generally improved the absorption of CUR, with medium-rigidity SPNPs bloomed maximum plasma concentration of CUR by 80.62-fold and showed the highest oral bioavailability. Results from monocultured and cocultured cell models demonstrated that medium-rigidity SPNPs were least influenced by the mucus layer and changes in rigidity significantly influenced the endocytosis and intracellular fate of SPNPs. Those with higher rigidity preferred to be endocytosed via a caveolae-mediated pathway and trafficked to the ER and Golgi, facilitating their whole transcytosis, and avoiding intracellular metabolism. Moreover, rigidity modulation efficiently induces the reversible opening of intercellular tight junctions, which synergistically improves the transport of CUR into blood circulation. This study suggested that rigidity regulation on food originated amphiphilic peptides could overcome multiple physiological barriers, showing great potential as natural building block toward oral delivery.
研究领域:
药剂学
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纳米技术
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药物递送系统
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生物物理学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2024
·
IF 7.7
Yadan Zhang,Xiaoyu Zhang,Tianhan Kai,Lin Zhang,Anping Li
Plant-derived exosome-like nanovesicles (ELNs) are nano-sized vesicles extracted from edible plants. Lycium ruthenicum Murray (LRM) has been gaining increasing attention due to its nutritional and medicinal value, but the ELNs in LRM has not been reported. In this study, LRM-ELNs were obtained, and the proteins, lipids, microRNAs (miRNAs) and active components in LRM tissues and LRM-ELNs was analyzed by LC-MS/MS, LC-MS, high-throughput sequencing techniques, and physical and chemical analysis. LRM-ELNs can be uptaken by PC12 cells through macropinocytosis and caveolin-mediated endocytosis primarily. Transcriptomic and western blot experiments indicate that LRM-ELNs can inhibit Aβ-induced apoptosis in PC12 cells through the MAPK and PI3K/AKT signaling pathways, with miRNAs playing a crucial role. These results indicate that LRM-ELNs have the protection effect on PC12 cells and can be considered as dietary supplements for alleviating neurodegenerative diseases.
研究领域:
神经科学
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药理学
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细胞生物学
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分子生物学
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PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2024
·
IF 13.3
Xiao-Lin Hou,Lin-Fang Tan,Xiao-Ting Xie,Bin Zhang,Qiong Wang,Kai Cheng,Jin-Xuan Fan,Tian-Cai Liu,Bo Liu
The peroxisome is an important organelle for H 2 O 2 metabolism and O 2 redistribution in organisms. Drawing inspiration from this biochemical pathway, a T4-Ce6-Cat-Lox (TCCL) simpler biomimetic peroxisome was constructed using the T4 phage’s Soc and Hoc sites to enhance photodynamic therapy (PDT). The cascading catalytic system of lactate oxidase (Lox) and catalase (Cat) was displayed on the phage architecture through in vitro phage display technology. 720 Lox molecules and 95 Cat molecules displayed on the T4 phage can be precisely controlled by the feed concentration. The enzymatic reaction of Lox, triggered by lactic acid in the tumor microenvironment, generated H 2 O 2 at the Soc site. Subsequently, the H 2 O 2 was decomposed into O 2 by Cat at the Hoc site. By manipulating the cascading catalytic system ratio of Lox and Cat to 7.5:1, the ROS generation efficiency of Ce6 was as high as 99.2 %, and the tumor inhibition rate reached 91.25 %. More importantly, the TCCL was constructed by natural T4 nanocarrier, exhibiting good biocompatibility and low immunogenicity in vivo . This study explored the construction of a simplified biomimetic peroxisome using the T4 phage display technology and provided a promising strategy for cascading catalytic system construction.
研究领域:
生物医学工程
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肿瘤学
·
酶工程
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DOI
高影响因子
CARBOHYDRATE POLYMERS
·
2024
·
IF 10.7
Junxi Liu,Xiaoke Zhang,Yan Liu,Zhijing Wu,Zheng Cui,Xianglin Pan,Yuheng Zheng,Jinglin Wang,Kaiping Wang,Yu Zhang
Recently, the intestinal lymphatic transport based on Peyer's patches (PPs) is emerging as a promising absorption pathway for natural polysaccharides. Herein, the aim of this study is to investigate the PP-based oral absorption of a pectic polysaccharide from Smilax china L. (SCLP), as well as its uptake and transport mechanisms in related immune cells. Taking advantages of the traceability of fluorescently labeled SCLP, we confirmed that SCLP could be absorbed into PPs and captured by their mononuclear phagocytes (dendritic cells and macrophages) following oral administration. Subsequently, the systematic in vitro study suggested that the endocytic mechanisms of SCLP by model mononuclear phagocytes (BMDCs and RAW264.7 cells) mainly involved caveolae-mediated endocytosis, macropinocytosis and phagocytosis. More importantly, SCLP directly binds and interacts with toll-like receptor 2 (TLR2) and galectin 3 (Gal-3) receptor, and was taken up by mononuclear phagocytes in receptor-mediated manner. After internalization, SCLP was intracellularly transported primarily through endolysosomal pathway and ultimately localized in lysosomes. In summary, this work reveals novel information and perspectives about the in vivo fate of SCLP, which will contribute to further research and utilization of SCLP and other pectic polysaccharides.
研究领域:
药理学
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免疫学
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胃肠病学
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DOI
PubMed
高影响因子
ACS Nano
·
2024
·
IF 15.8
Dan Yang,Yuqi Feng,Ying Yuan,Linxuan Zhang,Yao Zhou,Adam C. Midgley,Yanrong Wang,Ning Liu,Guoliang Li,Xiaolin Yao,Dechun Liu
The epithelial mucosa is a key biological barrier faced by gastrointestinal, intraoral, intranasal, ocular, and vaginal drug delivery. Ligand-modified nanoparticles demonstrate excellent ability on this process, but their efficacy is diminished by the formation of protein coronas (PCs) when they interact with biological matrices. PCs are broadly implicated in affecting the fate of NPs in vivo and in vitro, yet few studies have investigated PCs formed during interactions of NPs with the epithelial mucosa, especially mucus. In this study, we constructed transferrin modified NPs (Tf-NPs) as a model and explored the mechanisms and effects that epithelial mucosa had on PCs formation and the subsequent impact on the transcellular transport of Tf-NPs. In mucus-secreting cells, Tf-NPs adsorbed more proteins from the mucus layers, which masked, displaced, and dampened the active targeting effects of Tf-NPs, thereby weakening endocytosis and transcellular transport efficiencies. In mucus-free cells, Tf-NPs adsorbed more proteins during intracellular trafficking, which enhanced transcytosis related functions. Inspired by soft coronas and artificial biomimetic membranes, we used mucin as an “active PC” to precoat Tf-NPs (M@Tf-NPs), which limited the negative impacts of “passive PCs” formed during interface with the epithelial mucosa and improved favorable routes of endocytosis. M@Tf-NPs adsorbed more proteins associated with endoplasmic reticulum-Golgi functions, prompting enhanced intracellular transport and exocytosis. In summary, mucus shielded against the absorption of Tf-NPs, but also could be employed as a spear to break through the epithelial mucosa barrier. These findings offer a theoretical foundation and design platform to enhance the efficiency of oral-administered nanomedicines.
研究领域:
纳米技术
·
药学
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生物医学工程
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细胞生物学
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药物递送系统
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PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2025
·Vol. 23
·期 1
·1-20
·
IF 12.6
Wu Can,Zhang Xiao Wei,Wang Manman,Sun Jinpan,Chen Jianfei,Guan Yanbin,Pang Xin
Chemotherapy remains an effective treatment for colon cancer but is hampered by its limited response rate. Bioactive peptides, marked with intracellular transformations, have been reported as an effective approach to boosting chemotherapeutic activity. Herein, a promising trypsin-responsive bioactive peptide-based nanodrug is constructed, which could significantly prolong the drug retention time in vivo by cascading transformations and improve chemotherapeutic efficacy. Initially, 1-Pept co-assembles with Dox into a few nanofibers called 1-Pept/Dox NFs, inducing an enhanced cellular uptake via caveolae-mediated endocytosis by avoiding lysosomal degradation and further promoting perinuclear transportation, thus enlarging the drug efficacy in target areas. After nanofiber disassembly, the released 1-Pept converts into Pept under the catalysis of intracellular overexpressed trypsin, which then reassembles into denser Pept NFs, inducing a cascade of effects including disruption of the cytoskeleton, mitochondrial dysfunction, and activation of caspase-3. By the synergism of Pept NFs and Dox, caspase-3 can be further activated, and cause greater damage to nuclear, thereby leading to tumor ablation. As the first example of employing trypsin-mediated nanodrugs with cascading transformations to promote chemotherapeutic activity, this work promises a strategy for novel therapies for efficiently combating colon cancer. Graphical
研究领域:
药理学
·
肿瘤学
·
纳米医学
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DOI
PubMed
高影响因子
MACROMOLECULAR BIOSCIENCE
·
2026
·Vol. 26
·期 7
·e70220
·
IF 4.2
Luwei Zhang,Yuduo Gao,Zhenghao Hu,Yiqing Chen,Chengfan Wu,Qi Shuai,Yunfeng Yan
Nanoparticle (NP) carriers are critical for enhancing the stability and cellular uptake of mRNA, enabling its therapeutic potential. However, conventional mRNA NP carriers enter cells via endocytosis, followed by endosome-lysosome trafficking, which leads to inefficient mRNA release into the cytoplasm. This insufficient endosomal escape has become a challenge in improving mRNA delivery efficiency for polymer and lipid NP carriers. In this study, we design a novel class of lipoic acid derivative (LA-Der) composite NPs with surface disulfide bonds that anchor onto cell membranes through disulfide exchange with cell surface thiols, bypassing endosomal degradation and directly releasing mRNA into the cytoplasm. We synthesized 25 LA-Ders with diverse chemical structures via amidation and incorporated 10 kDa polyethyleneimine (PEI) to form composite NPs for optimal mRNA loading. In vitro optimization identified three LA-Der/PEI formulations, LA-4A1, LA-5A1, and LA-6A2, as the most effective for mRNA delivery. Mechanistic studies revealed that thiol-mediated uptake is the predominant internalization pathway, facilitating the bypass of endosomal barriers. In vivo experiments confirmed high luciferase expression in the spleen and liver following intravenous injection of NPs carrying luciferase mRNA. These LA-Der/PEI composite NPs provide a promising strategy for overcoming intracellular endosomal escape barriers, advancing the clinical translation of mRNA therapeutics.
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高影响因子
Materials Today Bio
·
2026
·
IF 11
Yongguo Xiang,Jiaojiao Kou,Huijie Cao,Yuhui Zhang,Hong Cheng,Tu Wang,Jialing Jiang,Shuren Pan,Juan Kang,Yuanfu Ding,Wenjuan Wan,Shijie Zheng,Man Li,Xiaobei Huang,Ke Hu
Ocular fundus diseases—including age-related macular degeneration and diabetic retinopathy—are leading causes of irreversible vision loss worldwide. Current macromolecular therapies require frequent intravitreal injections, which increase patient burden and complication risks. To address these limitations, we engineered a macrophage membrane-biomimetic nanovesicle encapsulating ranibizumab (designated M@R) for noninvasive ocular delivery and selective targeting of inflammatory lesions in the posterior segment. In vitro studies demonstrated that M@R retained potent cytokine-scavenging activity against key pro-inflammatory mediators, and the macrophage membrane coating significantly enhanced transcytosis-mediated transport of ranibizumab across ocular epithelial barriers. Ex vivo and in vivo studies confirmed that M@R is capable of noninvasive traversal of ocular barriers, achieving targeted delivery to inflammatory lesions within the fundus. In a laser-induced choroidal neovascularization (CNV) mouse model, topical ocular administration of M@R significantly reduced both the area and thickness of CNV, attributable to its dual anti-inflammatory and anti-VEGF activities. Although multiple dosing was required to achieve therapeutic efficacy comparable to that of a single intravitreal ranibizumab injection, M@R exhibited markedly improved safety profiles, with no observable local ocular toxicity or systemic adverse effects following repeated administration. Collectively, these findings establish macrophage membrane-coated nanovesicles as a promising platform for barrier-penetrating, inflammation-targeted delivery of biologics in the treatment of fundus diseases.
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高影响因子
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