CARCINOGENESIS
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2024
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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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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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TALANTA
·
2025
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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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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2026
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IF 8.7
Qiyuan Luo,Shiqiang Li,Chenglong Zhang,Yijing Chen,Yun Chen
ALP1 is a structurally defined polysaccharide isolated from Amomum villosum T.L. Wu fruits with an average molecular weight of 26.1 kDa. Previous studies have demonstrated that ALP1 promotes growth performance of piglet by regulating proliferation of intestinal epithelial cells. However, the molecular mechanism remains incompletely understood. In the present study, the absorbability of ALP1 by porcine small intestine epithelial cells and regulating mechanism of ALP1 on cell proliferation were investigated. The results showed that ALP1 resists gastrointestinal degradation and is efficiently absorbed by intestinal epithelial cells via endocytosis. Furthermore, ALP1 facilitates cell cycle progression through upregulating expressions of cdk4 and cyclin e , resulting in an increased proportion of cells in the S and G2/M phases. These findings provide insights into the cellular mechanisms underlying the growth-promoting effects of ALP1 and highlight the potential of dietary polysaccharides as functional agents for enhancing animal growth and gut health.
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Journal of the American Chemical Society
·
2026
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IF 16.6
Xiaofei Xin,Yifu Lyu,Huanyu Qin,Jinyu Dai,Di Wu,Yu Ding,Qiang Tian,Chao Qin,Na Li,Lifang Yin
The rational design of nonlamellar, multicompartment lipid nanoparticles (LNPs) offers a promising strategy for advancing nucleic acid delivery and immunotherapy. In this study, imidazole-based LNPs (A3-DM/DL-LNPs) with a mesoscopically disordered internal structure resembling the sponge phase were developed, enabling efficient codelivery of mRNA and STAT3-targeting siRNA (siSTAT3). Small-angle scattering analysis revealed a unique quasi-periodic arrangement in A3-DM/DL-LNPs, characterized by broader interdomain spacing and higher membrane heterogeneity compared to benchmark ALC-0315-LNPs, suggesting enhanced endocytosis efficiency and more favorable RNA encapsulation. The “M-shaped” polar headgroup, formed by a piperazine ring flanked by two imidazole moieties, promoted membrane interaction, cellular uptake, and transfection efficiency. In contrast, alternative LNPs with linear polar head structures (A3-SS/SM/SL-LNPs and A4-SS/SM/SL-LNPs) showed inferior delivery performance. Raman spectroscopy revealed that lipid spatial localization correlated with RNA expression in the spleen and lymph nodes, highlighting the importance of LNP structure in immune activation and targeting specific immune organs. Functionally, A3-DM/DL-LNPs restored dendritic cell (DC) antigen presentation, alleviated endoplasmic reticulum (ER) stress, and reversed T cell exhaustion in acute myeloid leukemia (AML), triggering strong immune responses and enhancing natural killer (NK) cell and T cell-mediated antileukemic activity, thereby improving therapeutic outcomes.
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Materials Today Bio
·
2026
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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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MACROMOLECULAR BIOSCIENCE
·
2026
·Vol. 26
·期 7
·e70220
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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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Materials Today Bio
·
2025
·
IF 10.2
Yushuang Wei,Wenwen Li,Rong Xu,Cheng Xu,Xiangyang Li,Ning Li,Fengdan Xu,Kai Yang,Bing Yuan
Recent studies have demonstrated that the human antimicrobial peptide LL37 plays a critical role in immune regulation under both normal physiological conditions and during disease progression, as evidenced by its elevated levels observed in various chronic inflammatory diseases. A deeper understanding of its mechanism is essential for elucidating associated physiological and pathological processes, as well as for designing effective immune adjuvants and clinical therapeutics. In this study, we report that LL37 facilitates the assembly of unmethylated CpG dinucleotides (CpG ODNs), a clinically relevant immune adjuvant, into non-crystalline nanoparticles (NPs) with controlled size and zeta potential in a charge ratio-dependent manner. These assembled NPs enter cells via receptor-mediated macropinocytosis, coupled with LL37-mediated membrane penetration, thereby significantly enhancing cellular uptake of CpG compared to CpG alone, which enters cells through clathrin-mediated endocytosis. Consequently, the enhanced internalization of LL37-CpG NPs markedly boosts TNF-α production (>3.5-fold) in macrophages through interactions with lysosomal TLR9. This immunostimulatory mechanism offers an alternative perspective on how LL37 modulates nucleic acid assembly and activates immune cells, providing guidance for the application of peptide-CpG ODN complexes in vaccine adjuvants and immune modulation for disease treatment.
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CARBOHYDRATE POLYMERS
·
2025
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IF 12.5
Jinyan Gu,Mouming Zhao,Lijun You,Lianzhu Lin
Rhamnogalacturonan-I type pectin polysaccharide from wolfberry has immunity activity, but its intestinal immunity activity and structure-activity relationship in the small intestine was still unclear. This study comparatively investigated the intestinal immune activity of wolfberry-derived high and low branched Rhamnogalacturonan-I type pectin polysaccharides (H-LBP and L-LBP) and explored the interaction mechanism with mechanical barrier. In the normal mechanical barrier model, both H-LBP and L-LBP could cross mechanical barrier with transport rates of 23.2 % and 25 %, thereby directly enhancing macrophage viability and phagocytic ability after crossing the mechanical barrier. The transport mechanism of H-LBP in mechanical barrier included the clathrin- and caveolin-mediated pathways. In the damaged mechanical barrier model, H-LBP could significantly enhance mechanical barrier integrity, reduce the production of neurotransmitter (NO) and inflammatory cytokine (TNF-α), thereby exerting indirectly intestinal immune activity. Transcriptome analysis showed that the interaction mechanism between H-LBP and damaged mechanical barrier mainly involved signaling pathway regulating cell growth and survival (PI3K-AKT). Western blot experiment and molecular docking simulation confirmed that H-LBP could reduce the expression of p-PI3K, p-AKT and cleaved Caspase3. H-LBP had stronger directly and indirectly intestinal immune activity than L-LBP. These findings were useful for the application of H-LBP in improving intestinal immunity oral formulations.
研究领域:
食品科学
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免疫学
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分子生物学
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CHEMICAL ENGINEERING JOURNAL
·
2025
·
IF 13.2
Xinchen Zhao,Liyan Qiu
Triple-negative breast cancer (TNBC) is associated with high invasiveness and mortality, with current immunotherapies offering limited clinical benefits. Reduced tumor immunogenicity and dendritic cell (DC) dysfunction are major contributors to tumor immune evasion. Herein, an alkaline phosphatase (ALP)-responsive nanovesicle system (P-DOX/IFN-γ), based on lipid-like polyphosphonitrile (PEBP), was developed for the co-delivery of doxorubicin hydrochloride (DOX) and interferon-γ (IFN-γ), aiming to enhance the therapeutic efficacy against TNBC. The phosphate ester structure facilitates nanovesicle formation and enables multiple interactions with both drugs, thereby efficiently achieving the synchronous encapsulation of DOX within the membrane and IFN-γ in the aqueous cavity. P-DOX/IFN-γ exhibits enhanced tumor targeting and ALP-responsive drug release within the tumor microenvironment. Mechanistically, DOX induces immunogenic cell death in tumor cells, while IFN-γ induces cell cycle arrest and upregulates major histocompatibility complex class I (MHC I) expression, synergistically enhancing tumor immunogenicity and promoting DC activation. As a result, P-DOX/IFN-γ significantly amplifies antitumor immunity and reduces long-term postoperative metastasis in the orthotopic 4T1 tumor model. Overall, this study provides a versatile nanoplatform and a promising immunotherapeutic strategy for TNBC and other poorly immunogenic tumors.
研究领域:
肿瘤学
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药剂学
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免疫学
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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
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纳米医学
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药物递送
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ADVANCED FUNCTIONAL MATERIALS
·
2025
·
IF 19
Yi Zhang,Hao Guo,Gang Wang,Fang Lan,Shiyong Zhang
The core challenge of H 2 S therapy is to supply H 2 S in a continuous and steady way. By self-polymerizing lipoic acid trisulfide, herein a new H 2 S donor called poly-lipoic acid trisulfide particles (pLATP) is developed with the steady H 2 S supply over 48 h at both cellular and animal levels, the longest time reported so far. Mechanistically, the pLATP high-efficiently enters the cytoplasm via the poly(trisulfides) mediated membrane penetration. In cells, thanks to the polymerized solid sphere structure, the pLATP releases H 2 S by a layer-by-layer decomposed way. Only when the outer layer decomposes, the inner layer can be exposed. After H 2 S release, the pLATP degrades to lipoic acid, which is not only a B vitamin, but also enhances the expression of 3-mercaptopyruvate sulfurtransferase, a H 2 S synthesizing enzyme promoting the production of endogenous H 2 S. The dual pathways of exogenous supplementation and endogenous recovery warrant the continuous and steady supply of H 2 S at the lesion site. As a proof of concept, the pLATP normalized cardiac function in rats with myocardial ischemia-reperfusion injury.
研究领域:
药理学
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生物化学
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纳米医学
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心脏病学
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高分子化学
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