ADVANCED FUNCTIONAL MATERIALS
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2026
·
IF 19.9
Xiaoxue He,Tian Liu,Mingjia Sun,Linsheng Wu,Yinghou Wang,Jingdong Xiao,Jin Sun,Qikun Jiang
Small interfering RNAs (siRNAs) have emerged as promising therapeutics for ulcerative colitis (UC) owing to their potent anti-inflammatory effects and favorable biocompatibility. However, effective oral siRNA delivery remains challenging due to limited inflammatory cell targeting, inefficient endosomal escape, and rapid degradation in the gastrointestinal tract. To overcome these barriers, we developed a nano-in-micro modular microbead system for colon-targeted delivery of siRNA against tumor necrosis factor-α (TNF-α). This platform integrates two key components: (i) a library of ginsenoside-based lipid nanoparticles (LNPs) generated by screening natural sterol analogues, among which ginsenoside Rg3-based LNPs (Rg3@siTNF-α) were identified as optimal carriers, enabling enhanced macrophage targeting via glucose transporter-1–mediated recognition and promoting endosomal escape by attenuating Niemann–Pick C1 (NPC1)–dependent recycling; and (ii) a calcium alginate (CA) shell that encapsulated Rg3@siTNF-α to form microbeads (CA@Rg3@siTNF-α), protecting the LNPs from premature degradation in the upper gastrointestinal tract. Upon colon-specific dissolution, CA@Rg3@siTNF-α released Rg3@siTNF-α, facilitating efficient macrophage uptake, rapid endosomal escape, and lipase-responsive siRNA release. Consequently, the microbeads alleviated UC by suppressing inflammation and oxidative stress, restoring epithelial barrier integrity, and rebalancing the gut microbiota. Collectively, this work presents a spatiotemporally controlled strategy for oral siRNA delivery with multi-mechanistic therapeutic actions.
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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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ACS Nano
·
2025
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IF 16
Yuai Li,Yunting Zhang,Jingwen Wang,Yujie Che,Tao Gong,Zhirong Zhang,Renhe Liu,Yao Fu
Selective autophagy relies on multivalent recognition by receptors like SQSTM1/p62 to form aggregates that cluster disperse organelles, undergoing liquid–liquid phase separation to facilitate their clearance and maintain cellular homeostasis. Inspired by this, we present the multivalent nanoparticle-based organelle targeting chimera (NanoTACOrg) to efficiently degrade organelles by flexibly clustering organelles for sequestration and facilitating targeted recruitment of autophagosomes. NanoTACOrg, assembled with a PLGA core, lysosomal escape modules, organelle-targeting modules, and LC3B binding modules, is programmed to selectively degrade various organelles, including mitochondria, endoplasmic reticulum, and Golgi apparatus. After endocytosis and lysosomal escape, NanoTACOrg targets subcellular compartments and mimics p62 aggregate-driven organelle clustering and degradation, without exhibiting the “hook effect”. Specifically, NanoTACMito-mediated mitochondrial degradation disrupts oxidative phosphorylation (OXPHOS) while enhancing compensatory glycolysis, thus sensitizing tumor cells to the glucose transporter 1 (GLUT1) inhibitor BAY-876. BAY-876 loaded NanoTACMito potently inhibits tumor growth, recurrence, and metastasis, demonstrating superior therapeutic efficacy by simultaneously targeting OXPHOS and glycolysis. These findings highlight the potential of NanoTACOrg as a versatile and effective platform for cancer therapy, particularly through organelle-specific degradation and metabolic reprogramming.
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International Journal of Pharmaceutics-X
·
2024
·
IF 5.2
Liangxing Tu,Ping Han,Yongbing Sun,Yi Jin,Kaili Hu,Meng Cheng,Yisen Shao,Jianfang Feng,Fangying Yuan
Many researchers have studied the oral absorption mechanisms yet, however, considering stabilizers often participate in the absorption process of nanocrystals, these known mechanisms may be incorrect. Hence in this study, we aimed to explore the correct absorption mechanism of nanocrystals by performing related studies on stabilizer-free nanocrystals. We firstly prepared stabilizer-free silymarin nanocrystals by high-pressure homogenization, and then performed absorption-related studies, such as solubility, dissolution rate, pharmacokinetic study, cellular uptake and intracellular transport. Results showed the stabilizer-free silymarin nanocrystals had an average particle size of (450.2 ± 4.46) nm, with PDI of 0.280 ± 0.021 and Zeta potential of −26.9 ± 2.4 mV. The conversion of silymarin crude drug to stabilizer-free silymarin nanocrystals increased the compound's solubility by 1.41 times, with a dissolution rate of 92.2 % in water within 30 min compared to 38.5 % for crude drugs. Pharmacokinetic studies showed the oral bioavailability of stabilizer-free silymarin nanocrystals was found to be 1.48 times greater than that of the crude drugs. The cell experimentation results demonstrated that the stabilizer-silymarin nanocrystals can improve uptake but have poor transmembrane transport properties. Most researchers believe that nanocrystals can enhance transmembrane transport of drugs via an endocytosis-mediated pathway. In fact, nanocrystals are indeed endocytosed more by the cells, but this transport pathway is poor because the cells lack the intracellular transport pathway to transport nanocrystals from the AP side to the BP side. Therefore, we believe that the intracellular transport of nanocrystals can be enhanced by modifications and other carriers if needed to improve nanocrystals' ability to promote oral absorption.
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Acta Pharmaceutica Sinica B
·
2025
·
IF 14.6
Shengnan Li,Wei Lv,Jiangna Xu,Jiaqing Yin,Yuqin Chen,Linfeng Liu,Xiang Cao,Wenjing Li,Zhen Li,Hua Chen,Hongliang Xin
Ischemic stroke is the leading cause of disability and mortality worldwide. The blood‒brain barrier (BBB) is the first line of defense after ischemic stroke. Disruption of the BBB induced by brain microvascular endothelial cells (BMECs) dysfunction is a key event that triggers secondary damage to the central nervous system, where blood-borne fluids and immune cells penetrate the brain parenchyma, causing cerebral edema and inflammatory response and further aggravating brain damage. Here, we develop a novel artificial mesenchymal stem cell (MSC) extracellular vesicles by integrating MSC membrane proteins into liposomal bilayers, which encapsulated miR-132-3p with protective effects on BMECs. The artificial extracellular vesicles (MSCo/miR-132-3p) had low immunogenicity to reduce non-specific clearance by the mononuclear phagocytosis system (MPS) and could target ischemia-injured BMECs. After internalization into the damaged BMECs, MSCo/miR-132-3p escaped the lysosomes via the H II phase transition of 1,2-dioleoyl -sn- glycero-3-phosphoethanolamine (DOPE) and decreased cellular reactive oxygen species (ROS) and apoptosis levels by regulating the RASA1/RAS/PI3K/AKT signaling pathway. In the transient middle cerebral artery occlusion (tMCAO) models, MSCo/miR-132-3p targeted impaired brain regions (approximately 9 times the accumulation of plain liposomes at 12 h), reduced cerebral vascular disruption, protected BBB integrity, and decreased infarct volume (from 44.95% to 6.99%).
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ACS Sensors
·
2023
·
IF 8.9
Nini Xin,Dong Gao,Borui Su,Ting Zhou,Yuda Zhu,Chengheng Wu,Dan Wei,Jing Sun,Hongsong Fan
Mitochondria play significant roles in maintaining a stable internal environment for cell metabolism. Hence, real-time monitoring of the dynamics of mitochondria is essential for further understanding mitochondria-related diseases. Fluorescent probes provide powerful tools for visualizing dynamic processes. However, most mitochondria-targeted probes are derived from organic molecules with poor photostability, making long-term dynamic monitoring challenging. Herein, we design a novel mitochondria-targeted probe based on carbon dots with high performance for long-term tracking. Considering that the targeting ability of CDs is related to surface functional groups, which are generally determined by the reaction precursors, we successfully constructed mitochondria-targeted O-CDs with emission at 565 nm through solvothermal treatment of m-diethylaminophenol. The O-CDs are bright with a high quantum yield of 12.61%, high mitochondria-targeting ability, and good stability. The O-CDs possess a high quantum yield (12.61%), specific mitochondria-targeting ability, and outstanding optical stability. Owing to the abundant hydroxyl and ammonium cations on the surface, O-CDs showed obvious accumulation in mitochondria with a high colocalization coefficient of up to 0.90 and remained steady even after fixation. Besides, O-CDs showed outstanding compatibility and photostability under various interruptions or long-time irradiation. Therefore, O-CDs are preferable for the long-term tracking of dynamic mitochondrial behavior in live cells. We first observed the mitochondrial fission and fusion behaviors in HeLa cells, and then, the size, morphology, and distribution of mitochondria in physiological or pathological conditions were clearly recorded. More importantly, we observed different dynamics interactions between mitochondria and lipid droplets during the apoptosis and mitophagy processes. This study provides a potential tool for exploring interactions between mitochondria and other organelles, further promoting the research on mitochondria-related diseases.
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Pharmaceutics
·
2023
·Vol. 15
·期 2
·670
·
IF 5.4
Wen-Juan Shen,Duo-Mei Tian,Le Fu,Biao Jin,Yu Liu,Yun-Sheng Xu,Yong-Bin Ye,Xiao-Bo Wang,Xiao-Jun Xu,Chun Tang,Fang-Ping Li,Chun-Fei Wang,Gang Wu,Le-Ping Yan
Cell-penetrating peptides (CPPs) are attractive non-viral gene delivery vectors due to their high transfection capacity and safety. Previously, we have shown that cell-penetrating peptide RALA can be a promising gene delivery vector for chronic wound regeneration application. In this study, we engineered a novel peptide called RALA-E by introducing elastin-derived VGVAPG fragment into RALA, in order to target the elastin-binding protein on the cell surface and thus improve delivery efficacy of RALA. The transfection efficiency of RALA-E was evaluated by transfecting the HEK-293T and HeLa cell lines cells with RALA-E/pDNA complexes and the flow-cytometry results showed that RALA-E significantly increased the transfection efficiency by nearly 20% in both cell lines compared to RALA. Inhibition of pDNA transfection on HEK-293T cells via chlorpromazine, genistein and mβCD showed that the inhibition extent in transfection efficiency was much less for RALA-E group compared to RALA group. In addition, RALA-E/miR-146a complexes showed up to 90% uptake efficiency in macrophages, and can escape from the endosome and enter the nucleus to inhibit the expression of inflammation genes. Therefore, the developed RALA-E peptide has high potential as a safe and efficient vector for gene therapy application.Keywords:cell-penetrating peptide;gene delivery;elastin-derived peptide;elastin-binding protein;immune modulation
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高影响因子
MOLECULES
·
2022
·Vol. 27
·期 23
·8200
·
IF 4.927
Qianqian Han,Tongtong Zhang,Meifang Wang,Fei Yan,Jiyang Liu
Rapid and highly sensitive quantitative analysis of chlorpromazine (CPZ) in human whole blood is of great importance for human health. Herein, we utilize the screen-printed carbon electrodes (SPCE) as the electrode substrates for growth of highly electroactive and antifouling nanocomposite materials consisting of vertically ordered mesoporous silica films (VMSF) and electrochemically reduced graphene oxide (ErGO) nanosheets. The preparation of such VMSF/ErGO/SPCE could be performed by using an electrochemical method in a few seconds and the operation is controllable. Inner ErGO layer converted from graphene oxide (GO) in the growth process of VMSF provides oxygen-containing groups and two-dimensional π-conjugated planar structure for stable fabrication of outer VMSF layer. Owing to the π-π enrichment and excellent electrocatalytic abilities of ErGO, electrostatic preconcentration and antifouling capacities of VMSF, and inherent disposable and miniaturized properties of SPCE, the proposed VMSF/ErGO/SPCE sensor could be applied for quantitative determination of CPZ in human whole blood with high accuracy and sensitivity, good stability, and low sample consumption.Keywords:vertically ordered mesoporous silica films;screen-printed carbon electrodes;electrochemically reduced graphene oxide;chlorpromazine;electrochemical sensors;human whole blood
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EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING
·
2022
·Vol. 49
·期 8
·2655-2667
·
IF 10.057
Hou Zhenyu,Zhou Mei,Ma Yuanyuan,Xu Xiaoxuan,Zhang Zhiqi,Lai Shiwei,Fan Wenpei,Xie Jinbing,Ju Shenghong
Purpose Radiation therapy (RT) and photodynamic therapy (PDT) are promising while challenging in treating tumors. The potential radiation resistance of tumor cells and side effects to healthy tissues restrict their clinical treatment efficacy. Effective delivery of therapeutic agents to the deep tumor tissues would be available for tumor-accurate therapy and promising for the tumor therapy. Thus, developing nanoprobes with effectively delivering radiotherapy sensitizers and photosensitizers to the interior of tumors is needed for the accurate combined RT and PDT of tumor. Methods The size-changeable nanoprobes of Gd 2 O 3 @BSA-BSA-Ce6 (BGBC) were synthesized with a crosslinking method. Magnetic resonance imaging (MRI) and in vivo near-infrared (NIR) imaging were measured to evaluate the nanoprobes’ tumor accumulation and intratumor penetration effect. The tumor suppression effect of combined RT and PDT with these nanoprobes was also studied for the 4T1 bearing Balb/c mice. Results The nanoprobes BGBC showed high tumor accumulation and disintegrated into small particles responding to the photo-irradiation-produced reactive oxygen species (ROS), allowing for tumor penetration. Abundant radiotherapy sensitizers and photosensitizers were delivered to the deep tumor tissues, which is available for the accurate therapy of tumor. In addition, the BGBC displayed outstanding MRI and fluorescence imaging effects for evaluating the biodistribution and tumor suppression effect of nanoprobes. Consequently, significant tumor suppression effect was obtained based on the accurate tumor treatment with the combined RT and PDT. Conclusion The designed size-changeable nanoprobes BGBC showed excellent tumor accumulation and deep tumor penetration, resulting in a significant tumor suppression effect based on the combined RT and PDT. This study provides a novel strategy for dual delivery of radiotherapy sensitizers and photosensitizers into the deep tumor tissues and is promising for the accurate theranostics of tumor.
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JOURNAL OF COLLOID AND INTERFACE SCIENCE
·
2022
·
IF 9.965
Lijuan Yang,Shaochi Liu,Tian Quan,Yongqing Tao,Meng Tian,Luchun Wang,Junji Wang,Dandan Wang,Die Gao
Aggregation-induced emission fluorescent carbon dots (AIE-CDs) have applications in the fields of multi-colour anti-counterfeiting, information encryption, and imaging. In this study, four AIE-CDs (B-AIE-CDs, G-AIE-CDs, Y-AIE-CDs, and O-AIE-CDs) with blue, green, yellow, and orange fluorescence at high concentrations were fabricated using crystal violet as a precursor, solutions with different sulfuric acid concentrations as solvents under different temperatures and reaction times for the first time. The structural properties and fluorescence behaviour of the AIE-CDs were investigated. The results revealed that the sulfuric acid concentration had a significant effect on the fluorescence colour of the AIE-CDs because sulfuric acid can affect the degree of carbonisation, the type and content of nitrogen. Moreover, the reaction temperature and time affected the surface-defect state and the degree of carbonisation of the AIE-CDs, which affected the emission wavelength and quantum yield (QY) of the AIE-CDs. Furthermore, to exploit the unique characteristics (polychromatic aggregation fluorescence and acid-sensitive properties) of the obtained-AIE-CDs, anti-counterfeiting and information encryption methodologies (i.e., acid-stimuli-response producing multi-colour fluorescence) were preliminarily developed. Finally, B-AIE-CDs with a high QY of 43.5% were successfully used for rapid cytoplasmic imaging, demonstrating their applicability in biological fields.
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INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2022
·
IF 6.51
Yu Zou,Quan Zhou,Yinan Zhao,Defu Zhi,Huiying Chen,Rui Wang,Benzhi Ju,Shubiao Zhang
Ionizable lipids are the leading vectors for gene therapy. Understanding the effects of molecular structure on efficient gene delivery is one of the most important challenges for maximizing the utility of such lipid vectors. We synthesized an array of pH-responsive and ionizable lipids to investigate the relationship between lipid structure and activity. The optimized lipid (EDM) has double tertiary amines in the headgroup and an ester linker. EDM exhibited efficient DNA and siRNA delivery to, and gene silencing of, A549 cells. EDM has a p K a value of 6.67, which enabled it to quickly escape from the endosome after entering the cell; the ester linkages rapidly degraded and enabled gene release into the cytoplasm. EDM also delivered IGF-1R siRNA to inhibit tumor growth and induce cancer cell apoptosis by efficient inhibition of IGF-1R expression in mice. Our study on the structure–activity relationships of ionizable lipids will facilitate clinical applications.
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Bosnian Journal of Basic Medical Sciences
·
2022
·
IF 3.759
Peng Hua,Donglin Yang,Ruie Chen,Peiqi Qiu,Meiwan Chen
Cationic polymer polyethylenimine (PEI) plays a crucial role in gene delivery. However, high molecular weight PEI leads to higher efficient transfection efficacy and higher cytotoxicity, while low molecular weight PEI exhibits lower transfection performance with lower toxicity. Therefore, effective chemical modification of PEI is required to enhance transfection activity and improve biocompatibility. Here, reactive oxygen species (ROS) responsive PEI-based fluorinated polymers (TKPF) with three degrees of fluorination (TKPF 12.5%, TKPF 25%, and TKPF 50%) were designed and synthesized by crosslinking low molecular weight PEI (PEI 1.8K) with a thioketal (TK) linker and then modifying heptafluorobutyric anhydride onto their surface. Fluorination reduced the positive charge density and endowed hydrophobic and lipophobic characteristics to resist serum interactions. The fluorophilic effect mediated efficient cellular uptake and endosomal escape while ROS-responsive TK linker allowed the polyplex disassembly to decrease the cytotoxicity of the polycations and improve the release of payloads at specific sites. TKPFs attained superior transfection efficiency in multiple cell lines (293TN cells and B16F10 cells) in vitro and showed excellent biocompatibility. TKPFs also exhibited great serum resistance in gene delivery and TKPF 50% transfected nearly 80% cells in the presence of 70% FBS. These results demonstrate that the fluorination and ROS responsiveness combined polycations are excellent gene-delivery vectors with serum-resistant capacity for further application.
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危险品化学品经营许可证（带存储）