Drug Delivery and Translational Research
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2025
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IF 5.5
Zhang Honglei,Ma Jingxuan,Jin Lijie,Ma Yuqing,Dong Kai,Li Jing,Yu Fei,Song Gengshen
Messenger RNA (mRNA) therapeutics have shown considerable promise across a wide range of medical applications with lipid nanoparticles (LNPs) emerging as the most clinically advanced mRNA delivery vehicles. However, the risk of off-target tissue delivery remains a concern, underscoring the need for diverse ionizable lipids to optimize LNP-based delivery systems. In this study, we designed and synthesized a library of 21 novel ionizable lipids and evaluated their potential for mRNA delivery. The resulting LNPs displayed favorable physicochemical properties and low cytotoxicity. In vitro transfection assay identified 3 high efficiency LNPs: YK-305, YK-310 and YK-319. In a mouse model, intramuscular injection of firefly luciferase (Fluc) mRNA-LNPs resulted in high transfection efficiency in muscle tissue, with significantly reduced gene expression in the liver. After encapsulating varicella zoster virus (VZV) glycoprotein E (gE)-encoding mRNA, the three LNP formulations induced robust humoral and cellular immune responses specific to the gE antigen, demonstrated improved selectivity and immunogenicity compared to SM-102, the ionizable lipid used in Moderna’s Spikevax. The safety of the gE-mRNA LNP formulations were subsequently demonstrated in a mouse model. Collectively, these findings provide a foundation for the optimization of tissue-targeting ionizable lipids and highlight their potential to advance mRNA-based vaccines in clinical applications. Graphical abstract
研究领域:
生物医学工程
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病毒学
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免疫学
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药学
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纳米技术
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PubMed
高影响因子
Biomaterials Research
·
2023
·Vol. 27
·期 1
·1-12
·
IF 11.3
Xu Xiaolin,Guan Wencai,Yu Xiaolei,Xu Guoxiong,Wang Chenglong
Background Protocell refers to the basic unit of life and synthetic molecular assembly with cell structure and function. The protocells have great applications in the field of biomedical technology. Simulating the morphology and function of cells is the key to the preparation of protocells. However, some organic solvents used in the preparation process of protocells would damage the function of the bioactive substance. Perfluorocarbon, which has no toxic effect on bioactive substances, is an ideal solvent for protocell preparation. However, perfluorocarbon cannot be emulsified with water because of its inertia. Methods Spheroids can be formed in nature even without emulsification, since liquid can reshape the morphology of the solid phase through the scouring action, even if there is no stable interface between the two phases. Inspired by the formation of natural spheroids such as pebbles, we developed non-interfacial self-assembly (NISA) of microdroplets as a step toward synthetic protocells, in which the inert perfluorocarbon was utilized to reshape the hydrogel through the scouring action. Results The synthetic protocells were successfully obtained by using NISA-based protocell techniques, with the morphology very similar to native cells. Then we simulated the cell transcription process in the synthetic protocell and used the protocell as an mRNA carrier to transfect 293T cells. The results showed that protocells delivered mRNAs, and successfully expressed proteins in 293T cells. Further, we used the NISA method to fabricate an artificial cell by extracting and reassembling the membrane, proteins, and genomes of ovarian cancer cells. The results showed that the recombination of tumor cells was successfully achieved with similar morphology as tumor cells. In addition, the synthetic protocell prepared by the NISA method was used to reverse cancer chemoresistance by restoring cellular calcium homeostasis, which verified the application value of the synthetic protocell as a drug carrier. Conclusion This synthetic protocell fabricated by the NISA method simulates the occurrence and development process of primitive life, which has great potential application value in mRNA vaccine, cancer immunotherapy, and drug delivery. Graphical Abstract
研究领域:
生物技术
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细胞生物学
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分子生物学
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药学
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癌症研究
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PubMed
高影响因子
MOLECULAR CELL
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2026
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IF 16
Wei-Ying Meng,Moping Xu,Shu-Xia Sun,Zhi-Yan Sun,Fan-Chen Wang,Yao Lu,Yangchan Li,Jiejun Shi,Jian-Huang Xue
Pseudouridines (ψ) in mRNA are linked to alternative splicing, but their regulatory mechanisms remain unclear due to the lack of known reader proteins. Here, we identify SMD2, a core spliceosomal component, as a direct ψ reader. Through in vitro and ex vivo assays, we show that SMD2 preferentially binds to ψ-modified RNA over unmodified uridines in human cells. Specifically, SMD2 collaborates with ψ synthase (PUS) family enzymes to regulate alternative splicing by recognizing ψ residues near exon-intron junctions. Notably, SNRPD2 , the gene encoding SMD2, is overexpressed in multiple cancers and is essential for tumor cell proliferation through modulating mRNA maturation. These findings establish a direct mechanistic link between ψ and spliceosomal function, which positions SMD2 as a key regulator of ψ-mediated splicing and a promising therapeutic target in cancer.
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高影响因子
Biomaterials Science
·
2026
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IF 6.1
Qi Wei,Ruoshui Li,Jiaqi Fan,Mengyuan Xu,Pengcheng Yuan,Jiwei Liu,Qian Wang,Youqing Shen,Nigel K. H. Slater,Jianbin Tang
Lipid nanoparticles (LNPs) have emerged as a promising platform for mRNA delivery with widespread applications across various fields, including gene editing, disease treatment, and vaccine development. Improving mRNA expression and enhancing immune responses are essential for expanding their application in mRNA vaccines. In this study, we synthesized and screened a library of guanidine-based lipids (GLs) as the fifth component to enhance LNP-mediated mRNA transfection. After screening, GL9, featuring symmetrical and long alkyl chains, was found to be the optimal fifth component for incorporation into LNPs at a 5% molar ratio to enhance mRNA expression. GL9 addition broadly improved transfection across diverse cell types and LNP formulations, without significantly altering LNP physicochemical properties. Incorporating GL9 into LNP also increased spleen-targeted mRNA expression by 12-fold via intraperitoneal injection and enhanced expression by 2.7-fold after intramuscular administration in vivo. Furthermore, GL9 promoted dendritic cells maturation, highlighting its potential as an adjuvant for mRNA vaccines. Thus, GLs, which enhance both transfection and immune activation, were incorporated into five-component LNPs to establish a promising platform for mRNA vaccines and therapeutics, offering an innovative strategy to optimize LNP-mediated mRNA delivery.
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高影响因子
ACS Applied Materials & Interfaces
·
2026
·
IF 7.8
Muyaxin Wang,Wenliang Xue,Jinyu Liu,Yuhao Jiang,Jianhong Luo,Shasha Shi,Xudong Yin,Xinsong Li
Diabetic foot ulcer (DFU) is a severe complication of diabetes, characterized by impaired healing due to chronic inflammation, poor blood vessel growth, and compromised cell function. To improve DFU healing, we create a FGF2 mRNA loaded liposome/exosome hybrid (FGF2-LEH) with dual functions of tissue regrowth and inflammation regulation. The FGF2-LEH was fabricated by incubating FGF2 mRNA with liposomes to form the FGF2-Lipo complex, followed by hybridization with platelet-rich plasma-derived exosomes (PRP-Exos) through freeze–thaw cycle and extrusion. Characterizations demonstrated that the FGF2-LEH had suitable particle size, high encapsulation efficiency, and biosafety. In vitro experiments revealed that FGF2-LEH enhanced the migration and tube formation of human umbilical vein endothelial cells, highlighting its pro-angiogenic potential. In both type 1 and type 2 diabetic mouse models, a single dose of FGF2-LEH greatly accelerated wound healing. After 15 days, the healing rate of the FGF2-LEH group exceeded 96% with improved granulation tissue growth, which was superior to that of control. Histopathological analysis further confirmed that FGF2-LEH promoted CD31+ angiogenesis, increased collagen deposition, and induced macrophages toward M2 polarization, thereby improving anti-inflammatory effect. Taken together, FGF2-LEH combining the advantages of PRP-Exos and FGF2 mRNA provides an approach for DFU treatment with translational potential for clinical application.
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高影响因子
EUROPEAN JOURNAL OF MEDICAL RESEARCH
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2026
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IF 4.8
Shuyu Zhao,Nan Lv,Tianyi Liu,Yuhong Sun,Peiling Li
Preeclampsia (PE), a rare complication with a high incidence and mortality rate, causes tremendous mental and physical impairment to pregnant women. Emerging studies have identified that PE was primarily induced by inadequate trophoblast migration and invasion. Poly(A) Binding Protein Cytoplasmic 1 (PABPC1) is a critical modulator of mRNA translation and stability, with established role in modulating proliferation, apoptosis, and invasion of tumor cells. Transmembrane BAX Inhibitor Motif Containing 4 (TMBIM4), which negatively regulates apoptosis, is downregulated in placental tissues of patients with early-onset preeclampsia (EOPE). Notably, 3'UTR motif of TMBIM4 mRNA contains PABPC1 binding site. Here, we investigated the functional role of PABPC1 on regulating proliferation and invasion of trophoblast cells, and how PABPC1 modulated mRNA stability of TMBIM4. HTR-8/SVneo cells transfected with silencing or overexpressed PABPC1 plasmid were applied as the in vitro model. The results revealed that PABPC1 facilitated cell proliferation, migration, and invasion as well as inhibited apoptosis. Moreover, Sprague Dawley rats were received intraperitoneal lipopolysaccharides administration at 40 μg/kg on gestational days 14.5, 15.5, and 16.5. Upregulated PABPC1 ameliorated elevated blood pressure and severe kidney impairment. Furthermore, for the rescue experiments, the effect of PABPC1 on boosting cell proliferation and invasion was blocked by silencing TMBIM4. More interestingly, according to RIP-qPCR and dual luciferase reporter assays, PABPC1 enhanced TMBIM4 expression through enhancing its mRNA stability via binding to its 3'UTR. Taken together, PABPC1 suppressed EOPE development through boosting trophoblast proliferation and invasion by elevating TMBIM4 mRNA stability. Our findings firstly elucidated the vital effect of PABPC1 on EOPE pathogenesis and highlighted that PABPC1 upregulation might be developed as a promising strategy for EOPE treatment.
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CELL BIOCHEMISTRY AND BIOPHYSICS
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2026
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IF 3
Chen Zhi,Liang Dan,Liu Zhai,Ren Yu,Wang Zhimei,Wan Jun,Tang Yi,Zhou Yibo
Nasopharyngeal carcinoma (NPC) remains a major clinical challenge, particularly at advanced stages. RNA-binding proteins (RBPs) are important post-transcriptional regulators of tumorigenesis, but their roles in NPC remain poorly understood. This study investigated whether RNA-binding motif protein 4 (RBM4) stabilizes homeobox B13 ( HOXB13 ) mRNA and thereby activates oncogenic signaling to promote NPC progression. Bioinformatics analysis identified differentially expressed genes in NPC. ENCORI was used to predict potential RNA-binding proteins (RBPs) targeting the candidate gene, and the predicted interaction was validated by RNA immunoprecipitation. Functional effects of HOXB13 and RBM4 in NPC cells were examined using colony formation and Transwell assays, along with modulating RBM4, HOXB13, nuclear factor kappa B (NF-κB) p65, and β-catenin expression. In vivo, effects of the RBM4/HOXB13 axis on NPC tumor growth and metastasis were evaluated using murine xenograft and lung metastasis models. HOXB13 was among the most strongly upregulated genes in NPC, and RBM4 was predicted to be a candidate RBP targeting HOXB13 mRNA. RBM4 was also upregulated in NPC models and increased HOXB13 mRNA stability. RBM4 silencing suppressed NPC cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT), while increasing apoptosis and reducing HOXB13 expression and NF-κB and Wnt/β-catenin signaling. Overexpression of HOXB13, NF-κB p65, or β-catenin partially reversed these effects. In vivo, RBM4 silencing inhibited xenograft growth and experimental lung metastasis, and these effects were partially reversed by HOXB13 overexpression. RBM4 acts as a pro-tumorigenic RBP in NPC by stabilizing HOXB13 mRNA and activating the NF-κB and Wnt/β-catenin pathways. The RBM4/HOXB13 axis therefore warrants further investigation as a potential molecular target in NPC.
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高影响因子
IMMUNOLOGIC RESEARCH
·
2023
·Vol. 71
·期 3
·356-372
·
IF 4.4
Lamprinou Malamatenia,Sachinidis Athanasios,Stamoula Eleni,Vavilis Theofanis,Papazisis Georgios
COVID-19 is an infectious disease caused by a single-stranded RNA (ssRNA) virus, known as SARS-CoV-2. The disease, since its first outbreak in Wuhan, China, in December 2019, has led to a global pandemic. The pharmaceutical industry has developed several vaccines, of different vector technologies, against the virus. Of note, among these vaccines, seven have been fully approved by WHO. However, despite the benefits of COVID-19 vaccination, some rare adverse effects have been reported and have been associated with the use of the vaccines developed against SARS-CoV-2, especially those based on mRNA and non-replicating viral vector technology. Rare adverse events reported include allergic and anaphylactic reactions, thrombosis and thrombocytopenia, myocarditis, Bell’s palsy, transient myelitis, Guillen-Barre syndrome, recurrences of herpes-zoster, autoimmunity flares, epilepsy, and tachycardia. In this review, we discuss the potential molecular mechanisms leading to these rare adverse events of interest and we also attempt an association with the various vaccine components and platforms. A better understanding of the underlying mechanisms, according to which the vaccines cause side effects, in conjunction with the identification of the vaccine components and/or platforms that are responsible for these reactions, in terms of pharmacovigilance, could probably enable the improvement of future vaccines against COVID-19 and/or even other pathological conditions.
研究领域:
免疫学
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分子生物学
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药理学
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PubMed
高影响因子
JOURNAL OF TRACE ELEMENTS IN MEDICINE AND BIOLOGY
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2023
·
IF 3.5
Peng-Cheng Xu,Chang-Chun Song,Xiao-Ying Tan,Tao Zhao,Chong-Chao Zhong,Jie-Jie Xu,Yu-Feng Song,Zhi Luo
Background Iron is an essential metal element for organisms, whose metabolism is regulated by many genes and also dietary iron sources. However, the characterization, distribution and the responses of iron metabolism-related genes to different iron sources were not clear in fish. Methods The full-length cDNA sequences of fifteen iron metabolism-relevant genes ( tf , tfr1 , hp , fpn1 , ho1 , ho2 , tfr2 , hjv , hepcidin , fth , ftl , ftm , irp1 , irp2 and hif2α .) were obtained via 3′ and 5′ RACE PCR from yellow catfish, a widely distributed freshwater teleost in China and other Asian countries. Their molecular characterizations were analyzed via the bioinformatic methods. Real-time quantitative PCR was used to explore their mRNA distribution in nine tissues. Their mRNA expression responses in four tissues (heart, brain, kidney and gill) were explored in yellow catfish fed diets with five iron sources, including ferrous sulfate (FeSO 4 ), ferrous bisglycinate (Fe-Gly), ferrous chloride (FeCl 2 ), ferric citrate (Fe-CA) and ferric oxide nanoparticles (Fe 2 O 3 NPs). Results Compared with mammals and other teleost, these members shared similar domains. Their mRNAs were expressed in nine tested tissues, but mRNA levels varied. Yellow catfish fed the diets containing Fe-Gly and Fe 2 O 3 NPs had higher iron contents in heart, brain, kidney and gill. Meantime, different dietary iron sources addition affected their mRNA expression differentially in brain, heart, kidney and gill. It should be pointed out that only three biological replicate tanks were used in the present feeding treatment , and more biological replicate tanks (more than five) should be emphasized in further researches. Conclusion Taken together, our study identified fifteen iron metabolism-relevant genes, explored their mRNA expression in nine tissues, and their mRNA expression in the responses to different dietary iron sources in four tissues, indicating their important regulatory function in iron metabolism and homeostasis.
研究领域:
水产养殖
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分子生物学
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营养学
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高影响因子
Acta Biomaterialia
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2017
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IF 6.319
Man Li,You Li,Ke Peng,Ying Wang,Tao Gong,Zhirong Zhang,Qin He,Xun Sun
Intranasal mRNA vaccination provides immediate immune protection against pandemic diseases. Recent studies have shown that diverse forms of polyethyleneimine (PEI) have potent mucosal adjuvant activity, which could significantly facilitate the delivery of intranasal mRNA vaccines. Nevertheless, optimizing the chemical structure of PEI to maximize its adjuvanticity and decrease its toxicity remains a challenge. Here we show that the chemical structure of PEI strongly influences how well nanocomplexes of PEI and mRNA migrate to the lymph nodes and elicit immune responses. Conjugating cyclodextrin (CD) with PEI600 or PEI2k yielded CP (CD-PEI) polymers with different CD/PEI ratios. We analyzed the delivery efficacy of CP600, CP2k, and PEI25k as intranasal mRNA vaccine carriers by evaluating the lymph nodes migration and immune responses. Among these polymers, CP2k/mRNA showed significantly higher in vitro transfection efficiency, stronger abilities to migrate to lymph nodes and stimulate dendritic cells maturation in vivo , which further led to potent humoral and cellular immune responses, and showed lower local and systemic toxicity than PEI25k/mRNA. These results demonstrate the potential of CD-PEI2k/mRNA nanocomplex as a self-adjuvanting vaccine delivery vehicle that traffics to lymph nodes with high efficiency. Statement of Significance As we face outbreaks of pandemic diseases such as Zika virus , intranasal mRNA vaccination provides instant massive protection against highly variant viruses. Various polymer-based delivery systems have been successfully applied in intranasal vaccine delivery. However, the influence of molecular structure of the polymeric carriers on the lymph node trafficking and dendritic cell maturation is seldom studied for intranasal vaccination. Therefore, engineering polymer-based vaccine delivery system and elucidating the relationship between molecular structure and the intranasal delivery efficiency are essential for maximizing the immune responses. We hereby construct self-adjuvanting polymer-based intranasal mRNA vaccines to enhance lymph node trafficking and further improve immune responses.
研究领域:
疫苗学
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药学
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免疫学
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聚合物化学
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PubMed
高影响因子
DEVELOPMENTAL CELL
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2020
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IF 10.092
Yongyan Tang,Chun-Chun Gao,Ying Gao,Ying Yang,Boyang Shi,Jia-Li Yu,Cong Lyu,Bao-Fa Sun,Hai-Lin Wang,Yunyuan Xu,Yun-Gui Yang,Kang Chong
Summary Extreme weather events can cause heat stress that decreases crop production. Recent studies have demonstrated that protein degradation and rRNA homeostasis as well as transcription factors are involved in the thermoresponse in plants. However, how RNA modifications contribute to temperature stress response in plant remains largely unknown. Herein, we identified OsNSUN2 as an RNA 5-methylcytosine (m 5 C) methyltransferase in rice. osnsun2 mutant displayed severe temperature- and light-dependent lesion-mimic phenotypes and heat-stress hypersensitivity. Heat stress enhanced the OsNSUN2-dependent m 5 C modification of mRNAs involved in photosynthesis and detoxification systems, such as β-OsLCY , OsHO2 , OsPAL1 , and OsGLYI4 , which increased protein synthesis. Furthermore, the photosystem of osnsun2 mutant was vulnerable to high ambient temperature and failed to undergo repair under tolerable heat stress. Thus, OsNSUN2 mutation reduced photosynthesis efficiency and accumulated excessive reactive oxygen species upon heat treatment. Our findings demonstrate an important mechanism of mRNA m 5 C-dependent heat acclimation in rice.
研究领域:
植物生物学
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分子遗传学
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农业科学
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PubMed
高影响因子
Pharmaceutics
·
2026
·Vol. 18
·期 4
·509
·
IF 6.9
Kangling Xu,Junyu Su,Hailin Ma,Yanxia Zhu
Background/Objectives:Bone-targeted drug delivery systems hold great promise for treating skeletal diseases, yet the optimal strategy for functionalizing lipid nanoparticles (LNPs) with bone-homing ligands remains insufficiently explored. Herein, we compared two alendronate sodium (Alen) modification approaches (pre-conjugation and post-conjugation) for constructing bone-targeted LNPs capable of delivering mRNA to skeletal tissues.Methods:LNPs were fabricated via microfluidic mixing, and the 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-polyethylene glycol-alendronate conjugate (DSPE-PEG-Alen) required for the pre-conjugation method was synthesized. The bone-targeting ability of LNPs prepared by the two Alen modification strategies was evaluated using anin vitrohydroxyapatite (HAP) binding assay. Furthermore, the physicochemical properties, bone-targeting performance, mRNA delivery efficiency, and biosafety of the LNPs prepared by the post-conjugation method were assessed through cellular uptake,in vivoimaging, and other methods.Results:Hydroxyapatite binding assays revealed that the post-conjugation strategy afforded significantly superior bone affinity compared to the pre-conjugation approach. In addition, ex vivo bone fragment binding experiments further confirmed that the bone-targeting LNPs prepared by the post-conjugation method exhibited stronger bone-binding capability compared to unmodified LNPs. The optimized Alen-LNPs demonstrated efficient cellular uptake and functional mRNA translation in bone marrow mesenchymal stem cells with negligible cytotoxicity.In vivostudies in mice confirmed the preferential accumulation of Alen-LNPs in bone tissues, with successful green fluorescent protein (GFP) mRNA translation detected in bone tissue sections. Histopathological analysis confirmed the biosafety of the formulation.Conclusions:This study establishes the post-conjugation strategy as the superior approach for Alen functionalization of LNPs, providing a robust and reproducible platform for bone-targeted mRNA therapeutics.
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高影响因子
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