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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MICROCHEMICAL JOURNAL
·
2025
·
IF 5.1
Jiajing Cai,Bei Xia,Haofei Ji,Xiuen Cao,Qubo Zhu,Chuanpin Chen
DNA methylation at specific CpG sites plays a critical role in the diagnosis and treatment of human diseases. In this study, we introduce a site-specific DNA methylation detection biosensor that leverages immune recognition and nonlinear hybridization chain reactions (NHCR). Since anti-methylcytosine antibodies are unable to recognize methylcytosine within a DNA duplex, we specifically target the CpG site by removing the guanine complementary to the target methylcytosine in the capture probe, thereby creating a protruding region accessible for antibody recognition. We utilized NHCR as a signal amplification strategy to enable site-specific DNA methylation detection under isothermal and enzyme-free conditions. The proposed method achieves a detection limit of 0.15 pM and can differentiate methylation levels as low as 0.1 %, even in the presence of a large excess of unmethylated DNA. This approach is capable of detecting DNA methylation at specific CpG sites in genomic DNA extracted from human hepatocellular carcinoma (HCC) tissues, showcasing its considerable potential for biological research and disease diagnosis.
研究领域:
分子生物学
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医学诊断
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表观遗传学
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AQUATIC TOXICOLOGY
·
2017
·
IF 4.129
Jiebo Lin,Caihong Wang,Jinfeng Liu,Randy A. Dahlgren,Weiming Ai,Aibing Zeng,Xuedong Wang,Huili Wang
Triclosan (TCS) exposure has widely adverse biological effects such as influencing biological reproduction and endocrine disorders. While some studies have addressed TCS-induced expression changes of miRNAs and their related down-stream target genes, no data are available concerning how TCS impairs miRNA expression leading us to study up-stream regulating mechanisms. Four miRNAs (miR-125b, miR-205, miR-142a and miR-203a) showed differential expression between TCS-exposure treatments and the control group; their functions mainly involved fatty acid synthesis and metabolism. TCS exposure led to the up-regulation of mature miR-125b that was concomitant with consistent changes in pri-mir-125b-1 and pri-mir-125b-3 among its 3 pri-mir-125bs. Up-regulation of miR-125b originated from direct shear processes involving the two up-regulated precursors, but not pri-mir-125b2. Increased expression of pri-mir-125b-1 and pri-mir-125b-3 resulted from nfe2l2- and c/ebpα-integration with positive control elements of promoters for the two precursors. The overexpression of transcriptional factors, nfe2l2 and c/ebpα, initiated the promoter activity for the miR-125b precursor. CpG islands and Nfe2l2 were involved in constitutive expression of mir-125b-1 and mir-125b-3 . The activities of two promoter regions, −487 to −1 bp for pri-mir-125b1 and −1327 to +14 bp for pri-mir-125b-3 having binding sites for NFE2 and Nfe2l2/MAF:NFE2, were higher than other regions, further demonstrating that the transcriptional factor Nfe2l2 was involved in the regulation of pri-mir-125b1 and pri-mir-125b-3. TCS’s estrogen activity resulted from its effects on GPER, a novel membrane receptor, rather than the classical ERα and ERβ. These results explain, to some extent, the up-stream mechanism for miR-125b up-regulation, and also provide a guidance to future mechanistic study on TCS-exposure.
研究领域:
毒理学
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分子生物学
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环境科学
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International Journal of Pharmaceutics-X
·
2026
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IF 7.9
Xiuyun Lin,Hui Li,Jie Liu,Guangfeng Wu,Liuqing Yao,Zhouwei Zhan,Xiufang Yang,Xiu Yang,Shuxian Cai,Na Yao,Fengfang Chen,Wenqiang Yan,Peng Lyu
Neoantigen peptides evade central thymic tolerance due to their absence in normal tissues, making neoantigen vaccines a leading strategy for personalized cancer immunotherapy. Although nanoparticle-based delivery systems are widely used to enhance neoantigen immunogenicity, traditional nanovaccines often incorporate multiple adjuvants and inert carriers, which could hinder efficient antigen delivery and raise biosafety concerns. Herein, we report a carrier-free neoantigen nanovaccine (CpG-2′F/Neo WD ), assembled via fluorination-induced self-assembly for hepatocellular carcinoma (HCC) immunotherapy. This nanovaccine is formed by the co-assembly of fluorinated CpG (CpG-2′F) with the HCC neoantigen peptide (Neo WD ), yielding nanoparticles of approximately 69 nm with a high Neo WD loading efficiency of 67.18 wt%. In vitro studies demonstrate that the nanovaccine potently facilitates dendritic cell uptake and promotes endosomal/lysosomal escape, enhancing antigen cross-presentation efficiency by 2.05-fold compared to the antigen group. In vivo , by efficiently targeting lymph nodes (LNs), the nanovaccine orchestrated both innate and adaptive immune responses against cancer cells, leading to the pronounced expansion of antigen-specific CD8 + T cells and memory T cells. In both prophylactic and therapeutic Hepa1–6 HCC models, this nanovaccine effectively suppressed the progression of poorly immunogenic HCC. Therefore, this study presents a facile, safe and potently immunogenic carrier-free nanovaccine platform for HCC immunotherapy.
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Nanoscale Research Letters
·
2018
·Vol. 13
·期 1
·1-12
·
IF 3.125
Zhang Xueyan,Wu Fengbo,Men Ke,Huang Rong,Zhou Bailin,Zhang Rui,Zou Rui,Yang Li
As a novel toll-like receptor 9 (TLR9) agonist, synthetic unmethylated cytosine-phosphate-guanine (CpG) oligodeoxynucleotides can stimulate a Th1 immune response and potentially be used as therapeutic agents or vaccine adjuvants for the treatment of cancer. However, some drawbacks of CpG limit their applications, such as rapid elimination by nuclease-mediated degradation and poor cellular uptake. Therefore, repeat high-dose drug administration is required for treatment. In this work, a CpG delivery system based on 3-aminopropyltriethoxysilane (APTES)-modified Fe 3 O 4 nanoparticles (FeNPs) was designed and studied for the first time to achieve better bioactivity of CpG. In our results, we designed FeNP-delivered CpG particles (FeNP/CpG) with a small average size of approximately 50 nm by loading CpG into FeNPs. The FeNP/CpG particle delivery system, with enhanced cell uptake of CpG in bone marrow-derived dendritic cells (BMDCs) in vitro and through intratumoral injection, showed significant antitumor ability by stimulating better humoral and cellular immune responses in C26 colon cancer and 4T1 breast cancer xenograft models in vivo over those of free CpG. Moreover, mice treated by FeNP/CpG particles had delayed tumor growth with an inhibitory rate as high as 94.4%. In addition, approximately 50% of the tumors in the C26 model appeared to regress completely. Similarly, there were lower pulmonary metastases and a 69% tumor inhibitory rate in the 4T1 breast cancer tumor model than those in the untreated controls. In addition to their effectiveness, the easy preparation, safety, and high stability of FeNP/CpG particles also make them an attractive antitumor immunotherapy.
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PeerJ
·
2026
·
IF 2.9
Wenyan Cui,Yongjian Cheng,Wenzhong Chen,Behloul Nouredine,Jing He,Yan Zuo,Yue Yang
The efficient delivery of CpG oligodeoxynucleotides (CpG ODN) adjuvants is constrained by the limited endosomal escape capability of lipid nanoparticles (LNPs). To evaluate this critical parameter, we constructed an in vitro escape evaluation platform that integrates serum protein corona simulation, a biomimetic phospholipid bilayer barrier, and pH regulation. This platform enables quantitative analysis of the transmembrane delivery mechanism of LNP-CpG ODN while overcoming limitations of cellular models for studying carrier-biointerface interactions. Through optimization of the biomimetic membrane formulation, an optimal balance between high vesicle stability (PDI < 0.18) and membrane fusion activity was achieved. Furthermore, a safer and more efficient preparation workflow was established by replacing chloroform with dichloromethane and eliminating the vacuum-drying step. Importantly, the results reported here identify the pH 6.0 microenvironment, which simulates late endosomal conditions, as the critical functional window for escape, with its efficiency showing a significant positive correlation with TLR9 pathway activation intensity ( r = 0.8978, p < 0.0001). Overall, this work establishes a dual-parameter correlation framework linking escape efficiency to immune activity, providing a new paradigm for the rational design and optimization of LNP delivery systems.
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ACS Nano
·
2025
·
IF 16
Qingfei Sun,Yueyue Gui,Chong Fan,Jiaxiong Li,Xiaomeng Tan,Chao Li,Jin Qiu,Jiehua Ma
Macrophages use pattern recognition receptors (PRRs) to recognize, capture, and phagocytize pathogens. Recreating artificial systems to mimic such receptors for manipulating macrophage predation is both scientifically exciting and technologically relevant to anti-infection. Nevertheless, fabricating synthetic PRR-mimicking receptors with a predictable and stable structure remains a challenge. Herein, we use circular aptamers as building blocks to create artificial DNA receptors (ADRs) that mimic the function of PRRs. After modification of ADRs on macrophages, they can stably recognize specific pathogens and promote the phagocytosis of macrophages, akin to natural PRRs. As dynamic structures, these ADRs can be flexibly activated or inactivated by external DNA molecules, akin to protein receptors responding to small-molecule ligands. Owing to the programmability of the DNA reaction, Boolean logic operations can be introduced to logically manipulate the predation behavior of macrophages, exhibiting the characteristics of artificial receptors. Furthermore, ADRs can be integrated with other functional DNA motifs, e.g., CpG DNA, to enhance the activation and antibacterial capacity of macrophages with higher efficiency. Overall, we believe that this artificial receptor not only broadens the application of DNA nanotechnology in cell biology but also contributes to ongoing efforts to remodel the innate immune system for fighting infection in consideration of the growing emergence of multidrug-resistant bacteria.
研究领域:
细胞生物学
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纳米技术
·
免疫学
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JOURNAL OF CONTROLLED RELEASE
·
2023
·
IF 10.8
Yingbo Jia,Jing Hu,Chaojie Zhu,Zijing Li,Xinyu Yang,Ruitian Liu,Linghui Zeng,Lingxiao Zhang
The poor cancer immunotherapy outcome has been closely related to immunosuppressive tumor microenvironment (TME), which usually inactivates the antitumor immune cells and leads to immune tolerance. Metalloimmunotherapy by supplementing nutritional metal ions into TME has emerged as a potential strategy to activate the tumor-resident immune cells. Herein, we engineered a magnesium-contained nano-aluminum adjuvant (NanoAlum) through hydrolyzing a mixture of Mg(OH) 2 and Al(OH) 3 , which has highly similar components to commercial Imject Alum. Peritumoral injection of NanoAlum effectively neutralized the acidic TME while releasing Mg 2+ to activate the tumor-resident T cells . Meanwhile, NanoAlum also blocked the autophagy pathway in tumor cells and subsequently induced cell apoptosis . The in vivo studies showed that merely peritumoral injection of NanoAlum successfully inhibited the growth of solid tumors in mice. On this basis, NanoAlum combined with chemical drug methotrexate or immunomodulatory adjuvant CpG further induced potent antigen-specific antitumor immunity. Overall, our study first provides a rational design for engineering tumor-targeted nanomodulator from clinical adjuvants to achieve effective cancer metalloimmunotherapy against solid tumors.
研究领域:
肿瘤学
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免疫疗法
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纳米技术
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癌症生物学
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Nature Biomedical Engineering
·
2018
·Vol. 2
·期 8
·611-621
·
IF 0
Chao Yu,Xu Ligeng,Liang Chao,Feng Liangzhu,Xu Jun,Dong Ziliang,Tian Longlong,Yi Xuan,Yang Kai,Liu Zhuang
Radiation therapy for cancer can lead to off-target toxicity and can be ineffective against hypoxic solid tumours and distant metastases. Here, we show that intratumoral injection, in mouse and rabbit xenografts and in patient-derived mouse xenografts, of a sodium alginate formulation containing catalase (Cat) labelled with the therapeutic 131 I radioisotope enables long-term relief of tumour hypoxia and complete tumour elimination at low radioactivity doses. On injection, the soluble polysaccharide rapidly transforms into a hydrogel in the presence of endogenous Ca 2+ , fixing 131 I-Cat within the tumours. We also show that local radiotherapy with a formulation that includes the immunostimulatory CpG oligonucleotide combined with systemic checkpoint-blockade therapy using an anti-CTLA-4 antibody leads to metastasis inhibition and protection against tumour rechallenge. The local therapy, which uses only biocompatible components, might enable new strategies for local tumour treatments that can be combined with systemic therapeutic responses, for the inhibition of tumour metastasis and the prevention of tumour recurrence in patients with advanced-stage cancer.
研究领域:
肿瘤学
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免疫学
·
放射医学
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PubMed
ADVANCED MATERIALS
·
2025
·
IF 26.8
Weiyu Chen,Yuan Wu,Jianhua Luo,Wei Wei,Qitao Hu,Yiming Xu,Xinjie Zheng,Zhouyi Sun,Lingge Yang,Junkang Ding,Liyun Xu,Shugao Han,Weibo Cai,Kai Wang
Interventional thermal therapy, such as radiofrequency ablation (RFA), is a preferred therapy for non-small cell lung cancer (NSCLC) patients. However, part of some patients will still suffer from tumor recurrence due to incomplete ablation (e.g., restricted thermal conductivity, etc.). Notably, RFA can evoke anti-tumor immunity by releasing tumor-associated antigens (TAAs), but this effect is weak. Herein, to boost thermal and immune therapeutic efficiency for complete tumor eradication, an effective nano-adjuvant (CpG-pIL12-LDHs, LC12), layered double hydroxides (LDHs) carrying immune stimulators, CpG ODN (CpG) and IL-12 plasmid (pIL-12), is developed, which is further integrated into a 3D-printed collar for eliciting potent thermotherapy and therapeutic vaccine against lung cancer. The as-prepared 3D-printed adjuvant collar (3D-LC12) can be attached to the RFA electronic needle and respond to the radiofrequency electrical field during treatment, enhancing ablation temperature, area, and nano-adjuvant's diffusion. After release from the temperature-sensitive collar, LC12 can form an in situ therapeutic cancer vaccine, activate APCs, and remodel the tumor microenvironment (TME), triggering a robust antitumor immune response. Therefore, the current study demonstrates a multi-functional 3D-printed adjuvant collar for efficient eradication of lung cancer via one-time RFA-integrated therapy, providing a novel combined strategy for interventional thermal therapy against tumors.
研究领域:
生物医学工程
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肿瘤学
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免疫治疗
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纳米技术
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3D打印
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介入放射学
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Advanced Science
·
2020
·Vol. 7
·期 19
·2001108
·
IF 15.84
Jianghua Wang,Shuang Wang,Tong Ye,Feng Li,Xiaoyong Gao,Yan Wang,Peng Ye,Shuang Qing,Changlong Wang,Hua Yue,Jie Wu,Wei Wei,Guanghui Ma
Nanovaccines have attracted booming interests in vaccinology studies, but the profound impacts of their delivery mode on immune response remain unrealized. Herein, immunostimulatory CpG-modified tumor-derived nanovesicles (CNVs) are used as a nanovaccine testbed to initially evaluate the impacts of three distinct delivery modes, including mono-pulse CNVs, staggered-pulse CNVs, and gel-confined CNVs. Fundamentally, delivery mode has enormous impacts on the immunomodulatory effects, altering the spatiotemporal distribution of nanovaccine residence and dendritic cell–T cell interaction in lymph nodes, and finally affecting subsequent T cell-mediated immune performance. As a result, the gel-confined delivery mode offers the best therapeutic performance in multiple tumor models. When extending evaluation to examine how the various delivery modes impact the performance of liposome-based nanovaccines, similar trends in intralymph node distribution and antitumor effect are observed. This work provides a strong empirical foundation that nanovaccine researchers should position delivery mode near the top of their considerations for the experimental design, which should speed up nanovaccine development and facilitate efficient selection of appropriate delivery modes in the clinic.
研究领域:
疫苗学
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免疫学
·
纳米技术
·
癌症研究
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BIOCONJUGATE CHEMISTRY
·
2020
·
IF 4.031
Pengyan Hao,Xiaoxiao Wu,Liwen Wang,Shaoyin Wei,Hongyan Xu,Wenjuan Huang,Yana Li,Tinghong Zhang,Xingjie Zan
Utilizing nanoparticles to deliver subunit vaccine is considered to be a promising strategy to improve immune response. However, currently reported systems suffered from one or more points, for example, delicate design on molecular structures and elaborate synthesis process, low antigen and/or adjuvant encapsulation efficiency, involvement of toxic materials, and denaturing of bioactivity of antigen and/or adjuvant. To address these issues, here, for the first time, we developed a one-pot method to produce a subunit vaccine by using hexa-histidine metal assembly (HmA) to codeliver tumor-associated antigens (GP100, a peptide KTWGQYWQV) and adjuvant (CpG). The generation of subunit vaccines was detailedly characterized by various techniques, including dynamic scatter, scanning electron microscopy, transmission electron microscopy, UV–visible spectroscopy, agarose gel electrophoresis, etc. HmA displayed high efficiency on encapsulating both subunits (GP100 and CpG) under mild conditions, and the generated subunit vaccine showed a pH-dependent release profile of loaded subunits. In the cellular tests, these subunit vaccines behaved with a quick endocytosis into immune cells and a fast endo/lysosomes escape, inducing maturation of antigen presentative cells and stimulating a potent cellular immune response. These results suggested that HmA is a robust platform for fabricating subunit vaccine, with immense potential for the immunotherapy of various diseases.
研究领域:
纳米技术
·
免疫学
·
药学
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高影响因子
危险品化学品经营许可证（带存储）