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Cambi, A., M. Lakadamyali, D. S. Lidke, and M. F. Garcia-Parajo. "Meeting Report - Visualizing signaling nanoplatforms at a higher spatiotemporal resolution." Journal of Cell Science 126, no. 17 (August 30, 2013): 3817–21. http://dx.doi.org/10.1242/jcs.137901.
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Kim, Hyosuk, Eun Hye Kim, Gijung Kwak, Sung-Gil Chi, Sun Hwa Kim, and Yoosoo Yang. "Exosomes: Cell-Derived Nanoplatforms for the Delivery of Cancer Therapeutics." International Journal of Molecular Sciences 22, no. 1 (December 22, 2020): 14. http://dx.doi.org/10.3390/ijms22010014.
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Exosomes are cell-secreted nanovesicles that naturally contain biomolecular cargoes such as lipids, proteins, and nucleic acids. Exosomes mediate intercellular communication, enabling the transfer biological signals from the donor cells to the recipient cells. Recently, exosomes are emerging as promising drug delivery vehicles due to their strong stability in blood circulation, high biocompatibility, low immunogenicity, and natural targeting ability. In particular, exosomes derived from specific types of cells can carry endogenous signaling molecules with therapeutic potential for cancer treatment, thus presenting a significant impact on targeted drug delivery and therapy. Furthermore, exosomes can be engineered to display targeting moieties on their surface or to load additional therapeutic agents. Therefore, a comprehensive understanding of exosome biogenesis and the development of efficient exosome engineering techniques will provide new avenues to establish convincing clinical therapeutic strategies based on exosomes. This review focuses on the therapeutic applications of exosomes derived from various cells and the exosome engineering technologies that enable the accurate delivery of various types of cargoes to target cells for cancer therapy.
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Rahbar Saadat, Yalda, and Jaleh Barar. "Exosomes as versatile nanoscaled biocompartments in cancer therapy and/or resistance." BioImpacts 12, no. 2 (January 29, 2022): 87–88. http://dx.doi.org/10.34172/bi.2022.24253.
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Cancer remains to be a major hurdle to global health. Exosomes as a versatile bio-derived platform, hold a bright prospect in nano-scaled delivery/targeting strategies. Shreds of evidence indicate that exosomes have a critical role in drug resistance in cancer cells through various mechanisms including shuttling of miRNAs, drug efflux transporters, and anti-apoptotic signaling. Exosomes’ cargo, particularly miRNAs, may exert both resistance and in a few cases sensitivity to the anticancer agents in targeted cells. Therefore, the source and components of the exosomes should be carefully considered before any application. Our aim in this editorial is to further highlight the role of exosomes in the development of resistance to therapy in cancer cells. As a new chapter for drug delivery, the challenges should be elucidated before exosomes emerge as novel nanoplatforms for cancer therapy.
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Tang, Yongquan, Yan Chen, Zhe Zhang, Bo Tang, Zongguang Zhou, and Haining Chen. "Nanoparticle-Based RNAi Therapeutics Targeting Cancer Stem Cells: Update and Prospective." Pharmaceutics 13, no. 12 (December 8, 2021): 2116. http://dx.doi.org/10.3390/pharmaceutics13122116.
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Cancer stem cells (CSCs) are characterized by intrinsic self-renewal and tumorigenic properties, and play important roles in tumor initiation, progression, and resistance to diverse forms of anticancer therapy. Accordingly, targeting signaling pathways that are critical for CSC maintenance and biofunctions, including the Wnt, Notch, Hippo, and Hedgehog signaling cascades, remains a promising therapeutic strategy in multiple cancer types. Furthermore, advances in various cancer omics approaches have largely increased our knowledge of the molecular basis of CSCs, and provided numerous novel targets for anticancer therapy. However, the majority of recently identified targets remain ‘undruggable’ through small-molecule agents, whereas the implications of exogenous RNA interference (RNAi, including siRNA and miRNA) may make it possible to translate our knowledge into therapeutics in a timely manner. With the recent advances of nanomedicine, in vivo delivery of RNAi using elaborate nanoparticles can potently overcome the intrinsic limitations of RNAi alone, as it is rapidly degraded and has unpredictable off-target side effects. Herein, we present an update on the development of RNAi-delivering nanoplatforms in CSC-targeted anticancer therapy and discuss their potential implications in clinical trials.
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Hattab, Dima, and Athirah Bakhtiar. "Bioengineered siRNA-Based Nanoplatforms Targeting Molecular Signaling Pathways for the Treatment of Triple Negative Breast Cancer: Preclinical and Clinical Advancements." Pharmaceutics 12, no. 10 (September 29, 2020): 929. http://dx.doi.org/10.3390/pharmaceutics12100929.
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Triple negative breast cancer (TNBC) is one of the most aggressive types of breast cancer. Owing to the absenteeism of hormonal receptors expressed at the cancerous breast cells, hormonal therapies and other medications targeting human epidermal growth factor receptor 2 (HER2) are ineffective in TNBC patients, making traditional chemotherapeutic agents the only current appropriate regimen. Patients’ predisposition to relapse and metastasis, chemotherapeutics’ cytotoxicity and resistance and poor prognosis of TNBC necessitates researchers to investigate different novel-targeted therapeutics. The role of small interfering RNA (siRNA) in silencing the genes/proteins that are aberrantly overexpressed in carcinoma cells showed great potential as part of TNBC therapeutic regimen. However, targeting specificity, siRNA stability, and delivery efficiency cause challenges in the progression of this application clinically. Nanotechnology was highlighted as a promising approach for encapsulating and transporting siRNA with high efficiency-low toxicity profile. Advances in preclinical and clinical studies utilizing engineered siRNA-loaded nanotherapeutics for treatment of TNBC were discussed. Specific and selective targeting of diverse signaling molecules/pathways at the level of tumor proliferation and cell cycle, tumor invasion and metastasis, angiogenesis and tumor microenvironment, and chemotherapeutics’ resistance demonstrated greater activity via integration of siRNA-complexed nanoparticles.
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Tavakol, Ashrafizadeh, Deng, Azarian, Abdoli, Motavaf, Poormoghadam, et al. "Autophagy Modulators: Mechanistic Aspects and Drug Delivery Systems." Biomolecules 9, no. 10 (September 25, 2019): 530. http://dx.doi.org/10.3390/biom9100530.
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Autophagy modulation is considered to be a promising programmed cell death mechanism to prevent and cure a great number of disorders and diseases. The crucial step in designing an effective therapeutic approach is to understand the correct and accurate causes of diseases and to understand whether autophagy plays a cytoprotective or cytotoxic/cytostatic role in the progression and prevention of disease. This knowledge will help scientists find approaches to manipulate tumor and pathologic cells in order to enhance cellular sensitivity to therapeutics and treat them. Although some conventional therapeutics suffer from poor solubility, bioavailability and controlled release mechanisms, it appears that novel nanoplatforms overcome these obstacles and have led to the design of a theranostic-controlled drug release system with high solubility and active targeting and stimuli-responsive potentials. In this review, we discuss autophagy modulators-related signaling pathways and some of the drug delivery strategies that have been applied to the field of therapeutic application of autophagy modulators. Moreover, we describe how therapeutics will target various steps of the autophagic machinery. Furthermore, nano drug delivery platforms for autophagy targeting and co-delivery of autophagy modulators with chemotherapeutics/siRNA, are also discussed.
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Bracamonte, Angel Guillermo. "Current Advances in Nanotechnology for the Next Generation of Sequencing (NGS)." Biosensors 13, no. 2 (February 12, 2023): 260. http://dx.doi.org/10.3390/bios13020260.
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This communication aims at discussing strategies based on developments from nanotechnology focused on the next generation of sequencing (NGS). In this regard, it should be noted that even in the advanced current situation of many techniques and methods accompanied with developments of technology, there are still existing challenges and needs focused on real samples and low concentrations of genomic materials. The approaches discussed/described adopt spectroscopical techniques and new optical setups. PCR bases are introduced to understand the role of non-covalent interactions by discussing about Nobel prizes related to genomic material detection. The review also discusses colorimetric methods, polymeric transducers, fluorescence detection methods, enhanced plasmonic techniques such as metal-enhanced fluorescence (MEF), semiconductors, and developments in metamaterials. In addition, nano-optics, challenges linked to signal transductions, and how the limitations reported in each technique could be overcome are considered in real samples. Accordingly, this study shows developments where optical active nanoplatforms generate signal detection and transduction with enhanced performances and, in many cases, enhanced signaling from single double-stranded deoxyribonucleic acid (DNA) interactions. Future perspectives on miniaturized instrumentation, chips, and devices aimed at detecting genomic material are analyzed. However, the main concept in this report derives from gained insights into nanochemistry and nano-optics. Such concepts could be incorporated into other higher-sized substrates and experimental and optical setups.
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Liang, Xinqiang, Mekhrdod S. Kurboniyon, Yuanhan Zou, Kezong Luo, Shuhong Fang, Pengle Xia, Shufang Ning, Litu Zhang, and Chen Wang. "GSH-Triggered/Photothermal-Enhanced H2S Signaling Molecule Release for Gas Therapy." Pharmaceutics 15, no. 10 (October 10, 2023): 2443. http://dx.doi.org/10.3390/pharmaceutics15102443.
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Traditional treatment methods for tumors are inefficient and have severe side effects. At present, new therapeutic methods such as phototherapy, chemodynamic therapy, and gasodynamic therapy have been innovatively developed. High concentrations of hydrogen sulfide (H2S) gas exhibit cancer-suppressive effects. Herein, a Prussian blue-loaded tetra-sulfide modified dendritic mesoporous organosilica (PB@DMOS) was rationally constructed with glutathione (GSH)-triggered/photothermal-enhanced H2S signaling molecule release properties for gas therapy. The as-synthesized nanoplatform confined PB nanoparticles in the mesoporous structure of organosilica silica due to electrostatic adsorption. In the case of a GSH overexpressed tumor microenvironment, H2S gas was controllably released. And the temperature increases due to the photothermal effects of PB nanoparticles, further enhancing H2S release. At the same time, PB nanoparticles with excellent hydrogen peroxide catalytic performance also amplified the efficiency of tumor therapy. Thus, a collective nanoplatform with gas therapy/photothermal therapy/catalytic therapy functionalities shows potential promise in terms of efficient tumor therapy.
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Pennisi, Rosamaria, Maria Musarra-Pizzo, Tania Velletri, Antonino Mazzaglia, Giulia Neri, Angela Scala, Anna Piperno, and Maria Teresa Sciortino. "Cancer-Related Intracellular Signalling Pathways Activated by DOXorubicin/Cyclodextrin-Graphene-Based Nanomaterials." Biomolecules 12, no. 1 (January 1, 2022): 63. http://dx.doi.org/10.3390/biom12010063.
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In the last decade, nanotechnological progress has generated new opportunities to improve the safety and efficacy of conventional anticancer therapies. Compared with other carriers, graphene nanoplatforms possess numerous tunable functionalities for the loading of multiple bioactive compounds, although their biocompatibility is still a debated concern. Recently, we have investigated the modulation of genes involved in cancer-associated canonical pathways induced by graphene engineered with cyclodextrins (GCD). Here, we investigated the GCD impact on cells safety, the HEp-2 responsiveness to Doxorubicin (DOX) and the cancer-related intracellular signalling pathways modulated by over time exposure to DOX loaded on GCD (GCD@DOX). Our studies evidenced that both DOX and GCD@DOX induced p53 and p21 signalling resulting in G0/G1 cell cycle arrest. A genotoxic behaviour of DOX was reported via detection of CDK (T14/Y15) activation and reduction of Wee-1 expression. Similarly, we found a cleavage of PARP by DOX within 72 h of exposure. Conversely, GCD@DOX induced a late cleavage of PARP, which could be indicative of less toxic effect due to controlled release of the drug from the GCD nanocarrier. Finally, the induction of the autophagy process supports the potential recycling of DOX with the consequent limitation of its toxic effects. Together, these findings demonstrate that GCD@DOX is a biocompatible drug delivery system able to evade chemoresistance and doxorubicin toxicity.
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Yan, Huimin, Ying Hu, Antonina Akk, Muhammad Farooq Rai, Hua Pan, Samuel A. Wickline, and Christine T. N. Pham. "Induction of WNT16 via Peptide-mRNA Nanoparticle-Based Delivery Maintains Cartilage Homeostasis." Pharmaceutics 12, no. 1 (January 17, 2020): 73. http://dx.doi.org/10.3390/pharmaceutics12010073.
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Osteoarthritis (OA) is a progressive joint disease that causes significant disability and pain and for which there are limited treatment options. We posit that delivery of anabolic factors that protect and maintain cartilage homeostasis will halt or retard OA progression. We employ a peptide-based nanoplatform to deliver Wingless and the name Int-1 (WNT) 16 messenger RNA (mRNA) to human cartilage explants. The peptide forms a self-assembled nanocomplex of approximately 65 nm in size when incubated with WNT16 mRNA. The complex is further stabilized with hyaluronic acid (HA) for enhanced cellular uptake. Delivery of peptide-WNT16 mRNA nanocomplex to human cartilage explants antagonizes canonical β-catenin/WNT3a signaling, leading to increased lubricin production and decreased chondrocyte apoptosis. This is a proof-of-concept study showing that mRNA can be efficiently delivered to articular cartilage, an avascular tissue that is poorly accessible even when drugs are intra-articularly (IA) administered. The ability to accommodate a wide range of oligonucleotides suggests that this platform may find use in a broad range of clinical applications.
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Balaure, Paul Cătălin, and Alexandru Mihai Grumezescu. "Recent Advances in Surface Nanoengineering for Biofilm Prevention and Control. Part I: Molecular Basis of Biofilm Recalcitrance. Passive Anti-Biofouling Nanocoatings." Nanomaterials 10, no. 6 (June 24, 2020): 1230. http://dx.doi.org/10.3390/nano10061230.
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Medical device-associated infections are becoming a leading cause of morbidity and mortality worldwide, prompting researchers to find new, more effective ways to control the bacterial colonisation of surfaces and biofilm development. Bacteria in biofilms exhibit a set of “emergent properties”, meaning those properties that are not predictable from the study of free-living bacterial cells. The social coordinated behaviour in the biofilm lifestyle involves intricate signaling pathways and molecular mechanisms underlying the gain in resistance and tolerance (recalcitrance) towards antimicrobial agents as compared to free-floating bacteria. Nanotechnology provides powerful tools to disrupt the processes responsible for recalcitrance development in all stages of the biofilm life cycle. The present paper is a state-of-the-art review of the surface nanoengineering strategies currently used to design antibiofilm coatings. The review is structurally organised in two parts according to the targeted biofilm life cycle stages and molecular mechanisms intervening in recalcitrance development. Therefore, in the present first part, we begin with a presentation of the current knowledge of the molecular mechanisms responsible for increased recalcitrance that have to be disrupted. Further, we deal with passive surface nanoengineering strategies that aim to prevent bacterial cells from settling onto a biotic or abiotic surface. Both “fouling-resistant” and “fouling release” strategies are addressed as well as their synergic combination in a single unique nanoplatform.
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Yao, Ke, Xin Liang, Guiyang Zhang, Yan Rong, Qiuxiang Zhang, Qiaobo Liao, Hong Zhang, Kai Xi, and Junming Wang. "Covalent Organic Framework (COF): A Drug and Carrier to Attenuate Retinal Ganglion Cells Death in an Acute Glaucoma Mouse Model." Polymers 14, no. 16 (August 10, 2022): 3265. http://dx.doi.org/10.3390/polym14163265.
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Purpose: We aim to investigate the use of covalent organic framework (COF) nanoparticles in the local treatment of glaucoma, both as a means of protecting retinal ganglion cells (RGCs), and as a carrier for delayed release of the medication rapamycin following a single intravitreal injection. Methods: a water-dispersible COF, and a COF-based nanoplatform for rapamycin release (COF-Rapa) was constructed. C57BL/6J mice were randomly divided into four groups: intravitreal injection of 1.5 µL normal saline (NS), COF (0.67 ng/µL), rapamycin (300 µM) or COF-Rapa (0.67 ng/µL-300 µM), respectively. The ischemia–reperfusion (I/R) model was established to mimic high intraocular pressure (IOP)-induced retinal injury in glaucoma. Labeling of RGCs by Fluoro-Gold and retinal electroretinogram were used to evaluate retinal function. Immunohistochemistry and Western blotting analyses of retinas were performed. Results: COF nanoparticles were delivered in vitro and in vivo. Six weeks after the COF injection, the number of RGCs was unaffected. In addition, the number of RBPMS-positive RGCs, GFAP-positive astrocytes and Iba1-positive microglia did not differ from the normal control. COF could effectively reduce RGCs death, improve phototransduction function and alleviate the overactivation of microglia compared to NS control after retinal I/R injury. Within six weeks, the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway in the retinas could be inhibited by a single intravitreal injection of COF-Rapa. Compared with single COF administration, COF-Rapa significantly reduced the inflammatory reaction after retinal I/R injury. Conclusions: COF may act as both an RGC protection agent and a carrier for prolonged rapamycin release. This research may lead to the development of novel RGC protection agents and drug delivery techniques, as well as the creation of multifunctional COF-based biomaterials for glaucoma retinopathy.
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Lei, Kai, Ruihao Liang, Jialu Liang, Nan Lu, Jing Huang, Ke Xu, Binghua Tan, et al. "CircPDE5A-encoded novel regulator of the PI3K/AKT pathway inhibits esophageal squamous cell carcinoma progression by promoting USP14-mediated de-ubiquitination of PIK3IP1." Journal of Experimental & Clinical Cancer Research 43, no. 1 (April 24, 2024). http://dx.doi.org/10.1186/s13046-024-03054-3.
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Abstract Background Esophageal squamous cell carcinoma (ESCC) is a common gastrointestinal tumor and has become an important global health problem. The PI3K/AKT signaling pathway plays a key role in the development of ESCC. CircRNAs have been reported to be involved in the regulation of the PI3K/AKT pathway, but the underlying mechanisms are unclear. Therefore, this study aimed to identify protein-coding circRNAs and investigate their functions in ESCC. Methods Differential expression of circRNAs between ESCC tissues and adjacent normal tissues was identified using circRNA microarray analysis. Thereafter, LC–MS/MS was used to identify circPDE5A-encoded novel protein PDE5A-500aa. Molecular biological methods were used to explore the biological functions and regulatory mechanisms of circPDE5A and PDE5A-500aa in ESCC. Lastly, circRNA-loaded nanoplatforms were constructed to investigate the therapeutic translation value of circPDE5A. Results We found that circPDE5A expression was down-regulated in ESCC cells and tissues and that it was negatively associated with advanced clinicopathological stages and poorer prognosis in ESCC. Functionally, circPDE5A inhibited ESCC proliferation and metastasis in vitro and in vivo by encoding PDE5A-500aa, a key regulator of the PI3K/AKT signaling pathway in ESCC. Mechanistically, PDE5A-500aa interacted with PIK3IP1 and promoted USP14-mediated de-ubiquitination of the k48-linked polyubiquitin chain at its K198 residue, thereby attenuating the PI3K/AKT pathway in ESCC. In addition, Meo-PEG-S–S-PLGA-based reduction-responsive nanoplatforms loaded with circPDE5A and PDE5A-500aa plasmids were found to successfully inhibit the growth and metastasis of ESCC in vitro and in vivo. Conclusion The novel protein PDE5A-500aa encoded by circPDE5A can act as an inhibitor of the PI3K/AKT signaling pathway to inhibit the progression of ESCC by promoting USP14-mediated de-ubiquitination of PIK3IP1 and may serve as a potential target for the development of therapeutic agents. Graphical Abstract The novel protein PDE5A-500aa encoded by circPDE5A can act as an inhibitor of the PI3K/AKT signaling pathway to inhibit the progression of esophageal squamous cell carcinoma.
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Tu, Zhaoxu, Ming Liu, Changyi Xu, Yi Wei, Tong Lu, Yongqiang Xiao, Hongxia Li, et al. "Functional 2D Nanoplatforms Alleviate Eosinophilic Chronic Rhinosinusitis by Modulating Eosinophil Extracellular Trap Formation." Advanced Science, March 13, 2024. http://dx.doi.org/10.1002/advs.202307800.
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AbstractThe therapeutic outcomes of patients with eosinophilic chronic rhinosinusitis (ECRS) remain unsatisfactory, largely because the underlying mechanisms of eosinophilic inflammation are uncertain. Here, it is shown that the nasal secretions of ECRS patients have high eosinophil extracellular trap (EET) and cell‐free DNA (cfDNA) levels. Moreover, the cfDNA induced EET formation by activating toll‐like receptor 9 (TLR9) signaling. After demonstrating that DNase I reduced eosinophilic inflammation by modulating EET formation, linear polyglycerol‐amine (LPGA)‐coated TiS2 nanosheets (TLPGA) as functional 2D nanoplatforms with low cytotoxicity, mild protein adsorption, and increased degradation rate is developed. Due to the more flexible linear architecture, TLPGA exhibited higher cfDNA affinity than the TiS2 nanosheets coated with dendritic polyglycerol‐amine (TDPGA). TLPGA reduced cfDNA levels in the nasal secretions of ECRS patients while suppressing cfDNA‐induced TLR9 activation and EET formation in vitro. TLPGA displayed exceptional biocompatibility, preferential nasal localization, and potent inflammation modulation in mice with eosinophilic inflammation. These results highlight the pivotal feature of the linear molecular architecture and 2D sheet‐like nanostructure in the development of anti‐inflammation nanoplatforms, which can be exploited for ECRS treatment.
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Xu, Shuaishuai, Huaxiang Xu, Wenquan Wang, Shuo Li, Hao Li, Tianjiao Li, Wuhu Zhang, Xianjun Yu, and Liang Liu. "The role of collagen in cancer: from bench to bedside." Journal of Translational Medicine 17, no. 1 (September 14, 2019). http://dx.doi.org/10.1186/s12967-019-2058-1.
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Abstract Collagen is the major component of the tumor microenvironment and participates in cancer fibrosis. Collagen biosynthesis can be regulated by cancer cells through mutated genes, transcription factors, signaling pathways and receptors; furthermore, collagen can influence tumor cell behavior through integrins, discoidin domain receptors, tyrosine kinase receptors, and some signaling pathways. Exosomes and microRNAs are closely associated with collagen in cancer. Hypoxia, which is common in collagen-rich conditions, intensifies cancer progression, and other substances in the extracellular matrix, such as fibronectin, hyaluronic acid, laminin, and matrix metalloproteinases, interact with collagen to influence cancer cell activity. Macrophages, lymphocytes, and fibroblasts play a role with collagen in cancer immunity and progression. Microscopic changes in collagen content within cancer cells and matrix cells and in other molecules ultimately contribute to the mutual feedback loop that influences prognosis, recurrence, and resistance in cancer. Nanoparticles, nanoplatforms, and nanoenzymes exhibit the expected gratifying properties. The pathophysiological functions of collagen in diverse cancers illustrate the dual roles of collagen and provide promising therapeutic options that can be readily translated from bench to bedside. The emerging understanding of the structural properties and functions of collagen in cancer will guide the development of new strategies for anticancer therapy.
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Yu, Qiuyu, Yue Gao, Waicong Dai, Danni Li, Lu Zhang, Meera Moydeen Abdul Hameed, Rui Guo, Min Liu, Xiangyang Shi, and Xueyan Cao. "Cell Membrane‐Camouflaged Chitosan‐Polypyrrole Nanogels Co‐Deliver Drug and Gene for Targeted Chemotherapy and Bone Metastasis Inhibition of Prostate Cancer." Advanced Healthcare Materials, April 6, 2024. http://dx.doi.org/10.1002/adhm.202400114.
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AbstractThe development of functional nanoplatforms to improve the chemotherapy outcome and inhibit distal cancer cell metastasis remains an extreme challenge in cancer management. In this work, we report a human‐derived PC‐3 cancer cell membrane‐camouflaged chitosan‐polypyrrole nanogel (CH‐PPy NG) platform, which can be loaded with chemotherapeutic drug docetaxel (DTX) and RANK siRNA for targeted chemotherapy and gene silencing‐mediated metastasis inhibition of late‐stage prostate cancer in a mouse model. The prepared NGs with a size of 155.8 nm show good biocompatibility, pH‐responsive drug release profile, and homologous targeting specificity to cancer cells, allowing for efficient and precise drug/gene co‐delivery. Through in‐vivo antitumor treatment in a xenografted PC‐3 mouse tumor model, we show that such a CH‐PPy NG‐facilitated co‐delivery system allows for effective chemotherapy to slow down the tumor growth rate, and effectively inhibits the metastasis of prostate cancer to the bone via downregulation of the RANK/RANKL signaling pathway. The created CH‐PPy NGs may be utilized as a promising platform for enhanced chemotherapy and anti‐metastasis treatment of prostate cancer.This article is protected by copyright. All rights reserved
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Xu, Shibo, Linna Chang, Yanan Hu, Xingjun Zhao, Shuocheng Huang, Zhenhua Chen, Xiuli Ren, and Xifan Mei. "Tea polyphenol modified, photothermal responsive and ROS generative black phosphorus quantum dots as nanoplatforms for promoting MRSA infected wounds healing in diabetic rats." Journal of Nanobiotechnology 19, no. 1 (November 10, 2021). http://dx.doi.org/10.1186/s12951-021-01106-w.
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Abstract Background Healing of MRSA (methicillin-resistant Staphylococcus aureus) infected deep burn wounds (MIDBW) in diabetic patients remains an obstacle but is a cutting-edge research problem in clinical science. Surgical debridement and continuous antibiotic use remain the primary clinical treatment for MIDBW. However, suboptimal pharmacokinetics and high doses of antibiotics often cause serious side effects such as fatal complications of drug-resistant bacterial infections. MRSA, which causes wound infection, is currently a bacterium of concern in diabetic wound healing. In more severe cases, it can even lead to amputation of the patient's limb. The development of bioactive nanomaterials that can promote infected wound healing is significant. Results The present work proposed a strategy of using EGCG (Epigallocatechin gallate) modified black phosphorus quantum dots (BPQDs) as therapeutic nanoplatforms for MIDBW to achieve the synergistic functions of NIR (near-infrared)-response, ROS-generation, sterilization, and promoting wound healing. The electron spin resonance results revealed that EGCG-BPQDs@H had a more vital photocatalytic ability to produce singlet oxygen than BPQDs@H. The inhibition results indicated an effective bactericidal rate of 88.6% against MRSA. Molecular biology analysis demonstrated that EGCG-BPQDs significantly upregulated CD31 nearly fourfold and basic fibroblast growth factor (bFGF) nearly twofold, which were beneficial for promoting the proliferation of vascular endothelial cells and skin epidermal cells. Under NIR irradiation, EGCG-BPQDs hydrogel (EGCG-BPQDs@H) treated MIDBW area could rapidly raise temperature up to 55 °C for sterilization. The MIBDW closure rate of rats after 21 days of treatment was 92.4%, much better than that of 61.1% of the control group. The engineered EGCG-BPQDs@H were found to promote MIDBW healing by triggering the PI3K/AKT and ERK1/2 signaling pathways, which could enhance cell proliferation and differentiation. In addition, intravenous circulation experiment showed good biocompatibility of EGCG-BPQDs@H. No significant damage to major organs was observed in rats. Conclusions The obtained results demonstrated that EGCG-BPQDs@H achieved the synergistic functions of photocatalytic property, photothermal effects and promoted wound healing, and are promising multifunctional nanoplatforms for MIDBW healing in diabetics. Graphical Abstract
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Chen, Xi, Zhijie Xu, Tongfei Li, Abhimanyu Thakur, Yu Wen, Kui Zhang, Yuanhong Liu, et al. "Nanomaterial-encapsulated STING agonists for immune modulation in cancer therapy." Biomarker Research 12, no. 1 (January 7, 2024). http://dx.doi.org/10.1186/s40364-023-00551-z.
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AbstractThe cGAS-STING signaling pathway has emerged as a critical mediator of innate immune responses, playing a crucial role in improving antitumor immunity through immune effector responses. Targeting the cGAS-STING pathway holds promise for overcoming immunosuppressive tumor microenvironments (TME) and promoting effective tumor elimination. However, systemic administration of current STING agonists faces challenges related to low bioavailability and potential adverse effects, thus limiting their clinical applicability. Recently, nanotechnology-based strategies have been developed to modulate TMEs for robust immunotherapeutic responses. The encapsulation and delivery of STING agonists within nanoparticles (STING-NPs) present an attractive avenue for antitumor immunotherapy. This review explores a range of nanoparticles designed to encapsulate STING agonists, highlighting their benefits, including favorable biocompatibility, improved tumor penetration, and efficient intracellular delivery of STING agonists. The review also summarizes the immunomodulatory impacts of STING-NPs on the TME, including enhanced secretion of pro-inflammatory cytokines and chemokines, dendritic cell activation, cytotoxic T cell priming, macrophage re-education, and vasculature normalization. Furthermore, the review offers insights into co-delivered nanoplatforms involving STING agonists alongside antitumor agents such as chemotherapeutic compounds, immune checkpoint inhibitors, antigen peptides, and other immune adjuvants. These platforms demonstrate remarkable versatility in inducing immunogenic responses within the TME, ultimately amplifying the potential for antitumor immunotherapy.
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Feng, Yanlin, Jianlin Wang, Jimin Cao, Fangfang Cao, and Xiaoyuan Chen. "Manipulating calcium homeostasis with nanoplatforms for enhanced cancer therapy." Exploration, October 10, 2023. http://dx.doi.org/10.1002/exp.20230019.
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AbstractCalcium ions (Ca2+) are indispensable and versatile metal ions that play a pivotal role in regulating cell metabolism, encompassing cell survival, proliferation, migration, and gene expression. Aberrant Ca2+ levels are frequently linked to cell dysfunction and a variety of pathological conditions. Therefore, it is essential to maintain Ca2+ homeostasis to coordinate body function. Disrupting the balance of Ca2+ levels has emerged as a potential therapeutic strategy for various diseases, and there has been extensive research on integrating this approach into nanoplatforms. In this review, the current nanoplatforms that regulate Ca2+ homeostasis for cancer therapy are first discussed, including both direct and indirect approaches to manage Ca2+ overload or inhibit Ca2+ signalling. Then, the applications of these nanoplatforms in targeting different cells to regulate their Ca2+ homeostasis for achieving therapeutic effects in cancer treatment are systematically introduced, including tumour cells and immune cells. Finally, perspectives on the further development of nanoplatforms for regulating Ca2+ homeostasis, identifying scientific limitations and future directions for exploitation are offered.
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Bracamonte, A. Guillermo. "Hybrid Nano-platforms, and Silica Nano-hole Particles Intended for Enhanced Energy Modes: Light Scattering Studies Towards Lasers Developments." Journal of Optics and Photonics Research, February 29, 2024. http://dx.doi.org/10.47852/bonviewjopr42022233.
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In this short review, it was communicated about the design and synthesis of optical active nanoplatforms for Light Scattering studies highlighting holed nanoarchitectures as main sources of potential additional resonances and enhanced phenomena. In this context, the nanoplatforms were based on varied materials such as silicon compounds, silica, modified organosilanes, Nobel metals, and organic materials as well; such molecular and polymeric spacers, chromophores, etc. By this manner it was discussed how it could be recorded Enhanced Light Scattering signalling from hybrid nanoplatforms and nano-Hole particles; from where it was produced constructive wavelengths with a consequent amplification. In this context it was afforded to the discussion of examples of Laser Light Scattering properties and optical approaches already developed. In addition it was showed new developments within nano-optics to be considered for further studies and applications. And, in this direction it was considered the study from single nanoplatforms towards higher sized modified surfaces and 3D substrates. In this manner, it was leaded to the design of nano-optical resonators as well as nano-arrays resonators. Thus, it was evaluated varied materials to incorporate and evaluate for the next generation of nano-optical platforms by controlling Nano-chemistry and beyond for targeted photo-physics. The variable materials showed differences between varied modes of resonances and expected performances.
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Li, Zimu, Zirui Chen, Kexin Shi, Ping Huang, Wenfeng Zeng, Qili Huang, Jingwen Peng, et al. "Polyphenol‐Based Self‐Assembled Nanomedicine for a Three‐Pronged Approach to Reversing Tumor Immunosuppression." Advanced Healthcare Materials, September 29, 2024. http://dx.doi.org/10.1002/adhm.202402127.
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AbstractThe challenges of multi‐pathway immune resistance and systemic toxicity caused by the direct injection of immune checkpoint inhibitors are critical factors that compromise the effectiveness of clinical immune checkpoint blockade therapy. In this context, natural polyphenols have been employed as the primary component to construct a targeted and acid‐responsive PD‐L1 antibody (αPD‐L1) delivery nanoplatform. This platform incorporates garcinol, an inhibitor of the Nuclear Factor Kappa‐B (NF‐κB) signaling pathway, to regulate pro‐tumor immune escape cytokines and regulatory T cells. Additionally, the nanoplatform has been verified to induce immunogenic cell death (ICD), which promotes the maturation of dendritic cells and enhances the activity of cytotoxic T lymphocytes. In vivo and in vitro experimental results demonstrated that the nanoplatform can boost the immune response through a PD‐L1 and NF‐κB blocking/ICD inducing three‐pronged strategy, thereby effectively combating tumor growth and metastasis.
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Jing, Yuan-Zhe, Shu-Jin Li, and Zhi-Jun Sun. "Gas and gas-generating nanoplatforms in cancer therapy." Journal of Materials Chemistry B, 2021. http://dx.doi.org/10.1039/d1tb01661j.
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Wang, Shuangling, Yalin Wang, Jie Lv, Chunzhe Xu, Yuxin Wei, Guiying Wang, and Meng Li. "Remote Manipulation of TRPV1 Signaling by Near‐Infrared Light‐Triggered Nitric Oxide Nanogenerators for Specific Cancer Therapy." Advanced Healthcare Materials, December 28, 2023. http://dx.doi.org/10.1002/adhm.202303579.
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AbstractSpecific activation of transient receptor potential vanilloid member 1 (TRPV1) channels provides a new avenue for cancer treatment by inducing excessive Ca2+ influx. However, controllable manipulation of TRPV1 signaling for clinical application has remained elusive due to the challenge in finding a mild and effective method of exerting external stimulus without adverse side effects in living systems. Herein, a TRPV1‐targeting near‐infrared (NIR) triggered nitric oxide (NO)‐releasing nanoplatform (HCuS@PDA‐TRPV1/BNN6) based on polydopamine (PDA) coated hollow copper sulfide nanoparticles (HCuS NPs) has been developed for specific cancer therapy. Upon NIR irradiation, the NO donor BNN6 encapsulated in NIR‐responsive nanovehicles can locally generate NO to activate TRPV1 channels and induce Ca2+ influx. This NIR controlled mode enables the nanoplatform to exert its therapeutic effects below the apoptotic threshold temperature (43°C), minimizing the photothermal damage to normal tissue. Integrating this special NO‐mediated therapy with HCuS NPs mediated chemodynamic therapy (CDT), our designed nanoplatform exhibits a boosted anticancer activity with negligible systematic toxicity. Together, this study provides a promising strategy for site‐specific cancer therapy by spatiotemporally controlled activation of surface ion channels, thus offering a solution to an unmet clinical need in cancer treatment.This article is protected by copyright. All rights reserved
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He, Qingbin, Runxiao Zheng, Junchi Ma, Luyang Zhao, Yafang Shi, and Jianfeng Qiu. "Responsive manganese-based nanoplatform amplifying cGAS-STING activation for immunotherapy." Biomaterials Research 27, no. 1 (April 15, 2023). http://dx.doi.org/10.1186/s40824-023-00374-x.
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Abstract Background The activation of the cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) signaling pathway has attracted great attention for its ability to up-regulate innate immune response and thus enhance cancer immunotherapy. However, many STING agonists limit the further advancement of immunotherapy due to weak tumor responsiveness or low activation efficiency. The responsive and effective activation of cGAS-STING signaling in tumors is a highly challenging process. Methods In this study, a manganese-based nanoplatform (MPCZ NPs) was constructed that could responsively and efficiently generate more manganese ions (Mn2+) and reactive oxygen species (ROS) to activate cGAS-STING signaling pathway. Briefly, manganese dioxide (MnO2) was loaded with zinc protoporphyrin IX (ZPP) molecule and coated by polydopamine (PDA) embedded with NH4HCO3 to obtain MPCZ NPs. Additionally, MPCZ NPs were evaluated in vitro and in vivo for their antitumor effects by methyl thiazolyl tetrazolium (MTT) assay and TUNEL assays, respectively. Results In this system, tumor responsiveness was achieved by exogenous (laser irradiation) and endogenous (high levels GSH) stimulation, which triggered the collapse or degradation of PDA and MnO2. Moreover, the release of Mn2+ augmented the cGAS-STING signaling pathway and enhanced the conversion of hydrogen peroxide (H2O2) to hydroxyl radical (·OH) under NIR laser irradiation. Furthermore, the release of ZPP and the elimination of GSH by MPCZ NPs inhibited HO-1 activity and prevented ROS consumption, respectively. Conclusions This adopted open source and reduce expenditure strategy to effectively generate more ROS and Mn2+ to responsively activate cGAS-STING signaling pathway, providing a new strategy for improving immunotherapy.
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Weng, Zhenzhen, Jing Ye, Changxiong Cai, Zikang Liu, Yuanyuan Liu, Yingying Xu, Jinghong Yuan, et al. "Inflammatory microenvironment regulation and osteogenesis promotion by bone-targeting calcium and magnesium repletion nanoplatform for osteoporosis therapy." Journal of Nanobiotechnology 22, no. 1 (June 5, 2024). http://dx.doi.org/10.1186/s12951-024-02581-7.
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AbstractOsteoporosis is the most common bone metabolic disease that affects the health of middle-aged and elderly people, which is hallmarked by imbalanced bone remodeling and a deteriorating immune microenvironment. Magnesium and calcium are pivotal matrix components that participate in the bone formation process, especially in the immune microenvironment regulation and bone remodeling stages. Nevertheless, how to potently deliver magnesium and calcium to bone tissue remains a challenge. Here, we have constructed a multifunctional nanoplatform composed of calcium-based upconversion nanoparticles and magnesium organic frameworks (CM-NH2-PAA-Ald, denoted as CMPA), which features bone-targeting and pH-responsive properties, effectively regulating the inflammatory microenvironment and promoting the coordination of osteogenic functions for treating osteoporosis. The nanoplatform can efficaciously target bone tissue and gradually degrade in response to the acidic microenvironment of osteoporosis to release magnesium and calcium ions. This study validates that CMPA possessing favorable biocompatibility can suppress inflammation and facilitate osteogenesis to treat osteoporosis. Importantly, high-throughput sequencing results demonstrate that the nanoplatform exerts a good inflammatory regulation effect through inhibition of the nuclear factor kappa-B signaling pathway, thereby normalizing the osteoporotic microenvironment. This collaborative therapeutic strategy that focuses on improving bone microenvironment and promoting osteogenesis provides new insight for the treatment of metabolic diseases such as osteoporosis.
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Liu, Yingying, Zhiyan Ma, Xin Wang, Jiaming Liang, Linlin Zhao, Yingyu Zhang, Jiayu Ren, Shuping Zhang, and Yajun Liu. "A Core‐Brush Nanoplatform with Enhanced Lubrication and Anti‐Inflammatory Properties for Osteoarthritis Treatment." Advanced Science, November 2024. http://dx.doi.org/10.1002/advs.202406027.
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AbstractOsteoarthritis (OA) is recognized as a highly friction‐related joint disease primarily associated with increased joint friction and inflammation due to pro‐inflammatory M1‐type macrophage infiltration in the articular cavity. Therefore, strategies to simultaneously increase lubrication and relieve inflammation to remodel the damaged articular microenvironment are of great significance for enhancing its treatment. Herein, a multifunctional core‐brush nanoplatform composed of a ROS‐scavenging polydopamine‐coated SiO2 core and lubrication‐enhancing zwitterionic poly(2‐methacryloyloxyethyl phosphorylcholine) (PMPC) brush and loaded with the anti‐inflammatory drug curcumin by a reactive oxygen species (ROS)‐liable conjugation (named as SiO2@PP‐Cur) is rationally designed. Benefiting from the grafted zwitterionic PMPC brush, a tenacious hydration layer with enhanced lubricity for reducing joint abrasions is developed. More importantly, based on the mono‐iodoacetic acid‐induced arthritis (MIA) rat model, intra‐articular injection of SiO2@PP‐Cur nanoplatform can effectively alleviate articular inflammation via promoting macrophage polarization from the pro‐inflammatory M1 to anti‐inflammatory M2 state by activating the nuclear factor erythroid 2‐related factor 2 (Nrf2) signaling pathway and attenuating the degradation of cartilage matrix, resulting in the remodeling of the damaged microenvironment into a pro‐regenerative microenvironment. As a result, SiO2@PP‐Cur can considerably inhibit OA progression. Therefore, the work may provide a novel strategy for the development of an advanced core‐brush nanoplatform for enhanced OA therapy.
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Hu, Jiateng, Zhijue Xu, Donghui Liao, Yihong Jiang, Hongji Pu, Zhaoyu Wu, Xintong Xu, et al. "An H2S‐BMP6 Dual‐Loading System with Regulating Yap/Taz and Jun Pathway for Synergistic Critical Limb Ischemia Salvaging Therapy." Advanced Healthcare Materials, August 3, 2023. http://dx.doi.org/10.1002/adhm.202301316.
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AbstractCritical limb ischemia, the final course of peripheral artery disease, is characterized by an insufficient supply of blood flow and excessive oxidative stress. H2S molecular therapy possesses huge potential for accelerating revascularization and scavenging intracellular reactive oxygen species (ROS). Moreover, it is found that BMP6 is the most significantly up‐expressed secreted protein‐related gene in HUVECs treated with GYY4137, a H2S donor, based on the transcriptome analysis. Herein, a UIO‐66‐NH2@GYY4137@BMP6 co‐delivery nanoplatform to strengthen the therapeutic effects of limb ischemia is developed. The established UIO‐66‐NH2@GYY4137@BMP6 nanoplatform exerts its proangiogenic and anti‐oxidation functions by regulating key pathways. The underlying molecular mechanisms of UIO‐66‐NH2@GYY4137@BMP6 dual‐loading system lie in the upregulation of phosphorylated YAP/TAZ and Jun to promote HUVECs proliferation and downregulation of phosphorylated p53/p21 to scavenge excessive ROS. Meanwhile, laser‐doppler perfusion imaging (LDPI), injury severity evaluation, and histological analysis confirm the excellent therapeutic effects of UIO‐66‐NH2@GYY4137@BMP6 in vivo. This work may shed light on the treatment of critical limb ischemia by regulating YAP, Jun, and p53 signaling pathways based on gas‐protein synergistic therapy.
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Wang, Yang, Xueru Zhou, Li Yao, Qin Hu, Haoran Liu, Guosheng Zhao, Kai Wang, Jun Zeng, Mingwei Sun, and Chuanzhu Lv. "Capsaicin Enhanced the Efficacy of Photodynamic Therapy Against Osteosarcoma via a Pro‐Death Strategy by Inducing Ferroptosis and Alleviating Hypoxia." Small, January 14, 2024. http://dx.doi.org/10.1002/smll.202306916.
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AbstractFerroptosis, a novel form of nonapoptotic cell death, can effectively enhance photodynamic therapy (PDT) performance by disrupting intracellular redox homeostasis and promoting apoptosis. However, the extremely hypoxic tumor microenvironment (TME) together with highly expressed hypoxia‐inducible factor‐1α (HIF‐1α) presents a considerable challenge for clinical PDT against osteosarcoma (OS). Hence, an innovative nanoplatform that enhances antitumor PDT by inducing ferroptosis and alleviating hypoxia is fabricated. Capsaicin (CAP) is widely reported to specifically activate transient receptor potential vanilloid 1 (TRPV1) channel, trigger an increase in intracellular Ca2+ concentration, which is closely linked with ferroptosis, and participate in decreased oxygen consumption by inhibiting HIF‐1α in tumor cells, potentiating PDT antitumor efficiency. Thus, CAP and the photosensitizer IR780 are coencapsulated into highly biocompatible human serum albumin (HSA) to construct a nanoplatform (CI@HSA NPs) for synergistic tumor treatment under near‐infrared (NIR) irradiation. Furthermore, the potential underlying signaling pathways of the combination therapy are investigated. CI@HSA NPs achieve real‐time dynamic distribution monitoring and exhibit excellent antitumor efficacy with superior biosafety in vivo. Overall, this work highlights a promising NIR imaging‐guided “pro‐death” strategy to overcome the limitations of PDT for OS by promoting ferroptosis and alleviating hypoxia, providing inspiration and support for future innovative tumor therapy approaches.
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Huang, Qili, Chendi Ding, Wenyan Wang, Li Yang, Yinglong Wu, Wenfeng Zeng, Zimu Li, et al. "An “AND” logic gate–based supramolecular therapeutic nanoplatform for combatting drug-resistant non–small cell lung cancer." Science Advances 10, no. 39 (September 27, 2024). http://dx.doi.org/10.1126/sciadv.adp9071.
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Despite targeted therapies like epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), non–small cell lung cancer (NSCLC) remains a clinical challenge due to drug resistance hampering their efficacy. Here, we designed an “AND” logic gate–based supramolecular therapeutic platform (HA-BPY-GEF-NPs) for the treatment of EGFR-TKI resistant NSCLC. This system integrates both internal and external stimuli–responsive mechanisms that need to be activated in a preset sequence, enabling it to precisely control drug release behavior for enhancing therapeutic precision. By programming the system to respond to sequential near-infrared (NIR) irradiation and enzyme (cathepsin B) inputs, the release of gefitinib is effectively confined to the tumor region. Moreover, the NIR irradiation induces reactive oxygen species production, suppressing tumor growth and inhibiting bypass signaling pathways. The designed drug delivery system offers a highly controlled and targeted therapeutic approach, effectively inhibiting tumor growth, suppressing bypass signaling pathways, and overcoming EGFR-TKI resistance, thus offering a potential solution for maximizing therapeutic benefits.
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Zuo, Tiantian, Jun Zhang, Jie Yang, Rui Xu, Zongwei Hu, Zhihua Wang, Huizi Deng, and Qi Shen. "On-Demand responsive nanoplatform mediated targeting CAFs and down-regulating mtROS-PYK2 signaling for antitumor metastasis." Biomaterials Science, 2021. http://dx.doi.org/10.1039/d0bm01878c.
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The desmoplastic tumor microenvironment (DTME), including overexpressed stromal cells and extracellular matrix, formed the first barrier for accumulation and penetration of nanoparticles in tumors, which compromised the therapeutic efficacy and...
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Yu, Wenyan, Chengyuan Che, Yi Yang, Yuzhen Zhao, Junjie Liu, Aibing Chen, and Jinjin Shi. "Bioactive Self‐Assembled Nanoregulator Enhances Hematoma Resolution and Inhibits Neuroinflammation in the Treatment of Intracerebral Hemorrhage." Advanced Science, November 8, 2024. http://dx.doi.org/10.1002/advs.202408647.
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AbstractHematoma and secondary neuroinflammation continue to pose a significant challenge in the clinical treatment of intracerebral hemorrhage (ICH). This study describes a nanoregulator formed through the self‐assembly of Mg2+ and signal regulatory protein α (SIRPα) DNAzyme (SDz), aimed at enhancing hematoma resolution and inhibiting neuroinflammation in the treatment of ICH. The structure of SDz collapses in response to the acidic endo/lysosomal microenvironment of microglia, releasing Mg2+ and the SIRPα DNAzyme. The Mg2+ then acts as a cofactor to activate the SIRPα DNAzyme. By blocking the CD47‐SIRPα signaling pathway, microglia can rapidly and effectively phagocytose red blood cells (RBCs), thereby promoting the clearance of the hematoma. Simultaneously, Mg2+ reset the microglia to the M2 phenotype by inhibiting the MYD88/MAPK/NF‐κB signaling pathway, thereby modulating the inflammatory microenvironment of ICH. This co‐delivery and synergistic strategy resulted in a significant reduction in hematoma size, decreasing from 11.90 to 5.84 mm3, and promoted recovery from ICH with minimal systemic side effects. This simple yet highly effective nanoplatform, which involves complex synergistic mechanisms, proves to be effective for ICH therapy and holds great promise for introducing novel perspectives into clinical and translational approaches for ICH.
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Fernandes, Donald A. "Review on Metal-Based Theranostic Nanoparticles for Cancer Therapy and Imaging." Technology in Cancer Research & Treatment 22 (January 2023). http://dx.doi.org/10.1177/15330338231191493.
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Theranostic agents are promising due to their ability to diagnose, treat and monitor different types of cancer using a variety of imaging modalities. The advantage specifically of nanoparticles is that they can accumulate easily at the tumor site due to the large gaps in blood vessels near tumors. Such high concentration of theranostic agents at the target site can lead to enhancement in both imaging and therapy. This article provides an overview of nanoparticles that have been used for cancer theranostics, and the different imaging, treatment options and signaling pathways that are important when using nanoparticles for cancer theranostics. In particular, nanoparticles made of metal elements are emphasized due to their wide applications in cancer theranostics. One important aspect discussed is the ability to combine different types of metals in one nanoplatform for use as multimodal imaging and therapeutic agents for cancer.
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Liu, Junzhao, Zuohong Wu, Yadong Liu, Zhu Zhan, Liping Yang, Can Wang, Qinqin Jiang, Haitao Ran, Pan Li, and Zhigang Wang. "ROS-responsive liposomes as an inhaled drug delivery nanoplatform for idiopathic pulmonary fibrosis treatment via Nrf2 signaling." Journal of Nanobiotechnology 20, no. 1 (May 6, 2022). http://dx.doi.org/10.1186/s12951-022-01435-4.
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Abstract Background Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic disease with pathophysiological characteristics of transforming growth factor-β (TGF-β), and reactive oxygen species (ROS)-induced excessive fibroblast-to-myofibroblast transition and extracellular matrix deposition. Macrophages are closely involved in the development of fibrosis. Nuclear factor erythroid 2 related factor 2 (Nrf2) is a key molecule regulating ROS and TGF-β expression. Therefore, Nrf2 signaling modulation might be a promising therapy for fibrosis. The inhalation-based drug delivery can reduce systemic side effects and improve therapeutic effects, and is currently receiving increasing attention, but direct inhaled drugs are easily cleared and difficult to exert their efficacy. Therefore, we aimed to design a ROS-responsive liposome for the Nrf2 agonist dimethyl fumarate (DMF) delivery in the fibrotic lung. Moreover, we explored its therapeutic effect on pulmonary fibrosis and macrophage activation. Results We synthesized DMF-loaded ROS-responsive DSPE-TK-PEG@DMF liposomes (DTP@DMF NPs). DTP@DMF NPs had suitable size and negative zeta potential and excellent capability to rapidly release DMF in a high-ROS environment. We found that macrophage accumulation and polarization were closely related to fibrosis development, while DTP@DMF NPs could attenuate macrophage activity and fibrosis in mice. RAW264.7 and NIH-3T3 cells coculture revealed that DTP@DMF NPs could promote Nrf2 and downstream heme oxygenase-1 (HO-1) expression and suppress TGF-β and ROS production in macrophages, thereby reducing fibroblast-to-myofibroblast transition and collagen production by NIH-3T3 cells. In vivo experiments confirmed the above findings. Compared with direct DMF instillation, DTP@DMF NPs treatment presented enhanced antifibrotic effect. DTP@DMF NPs also had a prolonged residence time in the lung as well as excellent biocompatibility. Conclusions DTP@DMF NPs can reduce macrophage-mediated fibroblast-to-myofibroblast transition and extracellular matrix deposition to attenuate lung fibrosis by upregulating Nrf2 signaling. This ROS-responsive liposome is clinically promising as an ideal delivery system for inhaled drug delivery. Graphical Abstract
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Li, Lin, Guangyu Rong, Xin Gao, Yiyun Cheng, Zhengwang Sun, Xiaopan Cai, and Jianru Xiao. "Bone‐Targeted Fluoropeptide Nanoparticle Inhibits NF‐κB Signaling to Treat Osteosarcoma and Tumor‐Induced Bone Destruction." Advanced Science, November 6, 2024. http://dx.doi.org/10.1002/advs.202412014.
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AbstractOsteosarcoma is a malignant bone cancer usually characterized by symptoms of bone loss due to pathologically enhanced osteoclast activity. Activated osteoclasts enhance bone resorption and promote osteosarcoma cell progression by secreting various cytokines. Intercepting the detrimental interplay between osteoclasts and osteosarcoma cells is considered as an option for osteosarcoma treatment. Here, a bone‐targeted fluoropeptide nanoparticle that can inhibit the nuclear factor kappa B (NF‐κB) signaling in both osteoclasts and osteosarcoma to address the above issue is developed. The NF‐κB essential modulator binding domain (NBD) peptide is conjugated with a fluorous tag to improve its proteolytic stability and intracellular penetration. The NBD peptide is efficiently delivered into cells after fluorination to induce apoptosis of osteocarcoma cells, and inhibits osteoclasts differentiation. The fluorous‐tagged NBD peptide is further co‐assembled with an oligo (aspartic acid) terminated fluoropeptide to form bone‐targeted peptide nanoparticles for osteosarcoma treatment. The targeted nanoparticles efficiently inhibited tumor progression and osteosarcoma‐induced bone destruction in vivo. This co‐assembled fluoropeptide nanoplatform proposed in this study offers a promising approach for targeted and intracellular delivery of peptide therapeutics in the treatment of various diseases.
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Wu, Ye, Jia‐Yi Lin, Yu‐Dong Zhou, Hai‐Jun Liu, Sheng‐Xin Lu, Xiao‐Kun Zhang, Ying‐Yun Guan, et al. "Oncolytic Peptide‐Nanoplatform Drives Oncoimmune Response and Reverses Adenosine‐Induced Immunosuppressive Tumor Microenvironment." Advanced Healthcare Materials, January 30, 2024. http://dx.doi.org/10.1002/adhm.202303445.
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AbstractThe application of oncolytic peptides has become a powerful approach to induce complete and long‐lasting remission in multiple types of carcinomas, as affirmed by the appearance of tumor‐associated antigens and adenosine triphosphate (ATP) in large quantities, which jumpstarts the cancer‐immunity cycle. However, the ATP breakdown product adenosine is a significant contributor to forming the immunosuppressive tumor microenvironment, which substantially weakens peptide‐driven oncolytic immunotherapy. In this study, a lipid‐coated micelle (CA@TLM) loaded with a stapled oncolytic peptide (PalAno) and an adenosine 2A receptor (A2AR) inhibitor (CPI‐444) is devised to enact tumor‐targeted oncolytic immunotherapy and to overcome adenosine‐mediated immune suppression simultaneously. The CA@TLM micelle accumulates in tumors with high efficiency, and the acidic lysosomal environment prompts the rapid release of PalAno and CPI‐444. Subsequently, PalAno induces swift membrane lysis of tumor cells and the release of antigenic materials. Meanwhile, CPI‐444 blocks activation of the immunosuppressive adenosine‐A2AR signaling pathway. This combined approach exhibit pronounced synergy at stalling tumor growth and metastasis in animal models for triple‐negative breast cancer (TNBC) and melanoma, providing a novel strategy for enhanced oncolytic immunotherapy.This article is protected by copyright. All rights reserved
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Cong, Yiyang, Bo Sun, Jianlun Hu, Xiaoyang Li, Yanan Wang, Jingyi Zhang, Dongzhi Yang, et al. "A carbon monoxide releasing metal organic framework nanoplatform for synergistic treatment of triple-negative breast tumors." Journal of Nanobiotechnology 20, no. 1 (November 24, 2022). http://dx.doi.org/10.1186/s12951-022-01704-2.
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Abstract Background Carbon monoxide (CO) is an important signaling molecule participating in multiple biological functions. Previous studies have confirmed the valuable roles of CO in cancer therapies. If the CO concentration and distribution can be controlled in tumors, new cancer therapeutic strategy may be developed to benefit the patient survival. Results In this study, a UiO-67 type metal–organic framework (MOF) nanoplatform was produced with cobalt and ruthenium ions incorporated into its structure (Co/Ru-UiO-67). Co/Ru-UiO-67 had a size range of 70–90 nm and maintained the porous structure, with cobalt and ruthenium distributed uniformly inside. Co/Ru-UiO-67 was able to catalyze carbon dioxide into CO upon light irradiation in an efficient manner with a catalysis speed of 5.6 nmol/min per 1 mg Co/Ru-UiO-67. Due to abnormal metabolic properties of tumor cells, tumor microenvironment usually contains abundant amount of CO2. Co/Ru-UiO-67 can transform tumor CO2 into CO at both cellular level and living tissues, which consequently interacts with relevant signaling pathways (e.g. Notch-1, MMPs etc.) to adjust tumor microenvironment. With proper PEGylation (pyrene-polyacrylic acid-polyethylene glycol, Py-PAA-PEG) and attachment of a tumor-homing peptide (F3), functionalized Co/Ru-UiO-67 could accumulate strongly in triple-negative MDA-MB-231 breast tumors, witnessed by positron emission tomography (PET) imaging after the addition of radioactive zirconium-89 (89Zr) into Co-UiO-67. When applied in vivo, Co/Ru-UiO-67 could alter the local hypoxic condition of MDA-MB-231 tumors, and work synergistically with tirapazamine (TPZ). Conclusion This nanoscale UiO-67 MOF platform can further our understanding of CO functions while produce CO in a controllable manner during cancer therapeutic administration. Graphical Abstract
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Xu, Zhijie, Zhiyang Zhou, Xiaoxin Yang, Abhimanyu Thakur, Ning Han, Hai-Tao Li, Liu-Gen Li, Jun Hu, Tong-fei Li, and Yuanliang Yan. "Determining M2 macrophages content for the anti-tumor effects of metal-organic framework-encapsulated pazopanib nanoparticles in breast cancer." Journal of Nanobiotechnology 22, no. 1 (July 20, 2024). http://dx.doi.org/10.1186/s12951-024-02694-z.
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AbstractPazopanib (PAZ), an oral multi-tyrosine kinase inhibitor, demonstrates promising cytostatic activities against various human cancers. However, its clinical utility is limited by substantial side effects and therapeutic resistance. We developed a nanoplatform capable of delivering PAZ for enhanced anti-breast cancer therapy. Nanometer-sized PAZ@Fe-MOF, compared to free PAZ, demonstrated increased anti-tumor therapeutic activities in both syngeneic murine 4T1 and xenograft human MDA-MB-231 breast cancer models. High-throughput single-cell RNA sequencing (scRNAseq) revealed that PAZ@Fe-MOF significantly reduced pro-tumorigenic M2-like macrophage populations at tumor sites and suppressed M2-type signaling pathways, such as ATF6-TGFBR1-SMAD3, as well as chemokines including CCL17, CCL22, and CCL24. PAZ@Fe-MOF reprogramed the inhibitory immune microenvironment and curbed tumorigenicity by blocking the polarization of M2 phenotype macrophages. This platform offers a promising and new strategy for improving the cytotoxicity of PAZ against breast cancers. It provides a method to evaluate the immunological response of tumor cells to PAZ-mediated treatment.
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Wang, Weimin, Yang Gao, Jianjun Xu, Tianhao Zou, Bin Yang, Shaobo Hu, Xiang Cheng, Yun Xia, and Qichang Zheng. "A NRF2 Regulated and the Immunosuppressive Microenvironment Reversed Nanoplatform for Cholangiocarcinoma Photodynamic‐Gas Therapy." Advanced Science, February 2, 2024. http://dx.doi.org/10.1002/advs.202307143.
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AbstractPhotodynamic therapy (PDT) is a minimally invasive and controllable local cancer treatment for cholangiocarcinoma (CCA). However, the efficacy of PDT is hindered by intratumoral hypoxia and the presence of an antioxidant microenvironment. To address these limitations, combining PDT with gas therapy may be a promising strategy to enhance tumor oxygenation. Moreover, the augmentation of oxidative damage induced by PDT and gas therapy can be achieved by inhibiting NRF2, a core regulatory molecule involved in the antioxidant response. In this study, an integrated nanotherapeutic platform called CMArg@Lip, incorporating PDT and gas therapies using ROS‐responsive liposomes encapsulating the photosensitizer Ce6, the NO gas‐generating agent L‐arginine, and the NRF2 inhibitor ML385, is successfully developed. The utilization of CMArg@Lip effectively deals with challenges posed by tumor hypoxia and antioxidant microenvironment, resulting in elevated levels of oxidative damage and subsequent induction of ferroptosis in CCA. Additionally, these findings suggest that CMArg@Lip exhibits notable immunomodulatory effects, including the promotion of immunogenic cell death and facilitation of dendritic cell maturation. Furthermore, it contributes to the anti‐tumor function of cytotoxic T lymphocytes through the downregulation of PD‐L1 expression in tumor cells and the activation of the STING signaling pathway in myeloid‐derived suppressor cells, thereby reprogramming the immunosuppressive microenvironment via various mechanisms.
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Zhang, Zhuhong, Shengjun Peng, Tengyan Xu, Jia Liu, Laien Zhao, Hui Xu, Wen Zhang, Yuanying Zhu, and Zhimou Yang. "Retinal Microenvironment‐Protected Rhein‐GFFYE Nanofibers Attenuate Retinal Ischemia‐Reperfusion Injury via Inhibiting Oxidative Stress and Regulating Microglial/Macrophage M1/M2 Polarization." Advanced Science, August 31, 2023. http://dx.doi.org/10.1002/advs.202302909.
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AbstractRetinal ischemia is involved in the occurrence and development of various eye diseases, including glaucoma, diabetic retinopathy, and central retinal artery occlusion. To the best of our knowledge, few studies have reported self‐assembling peptide natural products for the suppression of ocular inflammation and oxidative stress. Herein, a self‐assembling peptide GFFYE is designed and synthesized, which can transform the non‐hydrophilicity of rhein into an amphiphilic sustained‐release therapeutic agent, and rhein‐based therapeutic nanofibers (abbreviated as Rh‐GFFYE) are constructed for the treatment of retinal ischemia‐reperfusion (RIR) injury. Rh‐GFFYE significantly ameliorates oxidative stress and inflammation in an in vitro oxygen‐glucose deprivation (OGD) model of retinal ischemia and a rat model of RIR injury. Rh‐GFFYE also significantly enhances retinal electrophysiological recovery and exhibits good biocompatibility. Importantly, Rh‐GFFYE also promotes the transition of M1‐type macrophages to the M2 type, ultimately altering the pro‐inflammatory microenvironment. Further investigation of the treatment mechanism indicates that Rh‐GFFYE activates the PI3K/AKT/mTOR signaling pathway to reduce oxidative stress and inhibits the NF‐κB and STAT3 signaling pathways to affect inflammation and macrophage polarization. In conclusion, the rhein‐loaded nanoplatform alleviates RIR injury by modulating the retinal microenvironment. The findings are expected to promote the clinical application of hydrophobic natural products in RIR injury‐associated eye diseases.
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Zhao, Li, Fei Chang, Yao Tong, Jiawei Yin, Jiawen Xu, Hui Li, Lutao Du, and Yanyan Jiang. "A Multifunctional Bimetallic Nanoplatform for Synergic Local Hyperthermia and Chemotherapy Targeting HER2‐Positive Breast Cancer." Advanced Science, February 21, 2024. http://dx.doi.org/10.1002/advs.202308316.
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AbstractAnti‐HER2 (human epidermal growth factor receptor 2) therapies significantly increase the overall survival of patients with HER2‐positive breast cancer. Unfortunately, a large fraction of patients may develop primary or acquired resistance. Further, a multidrug combination used to prevent this in the clinic places a significant burden on patients. To address this issue, this work develops a nanotherapeutic platform that incorporates bimetallic gold‐silver hollow nanoshells (AuAg HNSs) with exceptional near‐infrared (NIR) absorption capability, the small‐molecule tyrosine kinase inhibitor pyrotinib (PYR), and Herceptin (HCT). This platform realizes targeted delivery of multiple therapeutic effects, including chemo‐and photothermal activities, oxidative stress, and immune response. In vitro assays reveal that the HCT‐modified nanoparticles exhibit specific recognition ability and effective internalization by cells. The released PYR inhibit cell proliferation by downregulating HER2 and its associated pathways. NIR laser application induces a photothermal effect and tumor cell apoptosis, whereas an intracellular reactive oxygen species burst amplifies oxidative stress and triggers cancer cell ferroptosis. Importantly, this multimodal therapy also promotes the upregulation of genes related to TNF and NF‐κB signaling pathways, enhancing immune activation and immunogenic cell death. In vivo studies confirm a significant reduction in tumor volume after treatment, substantiating the potential effectiveness of these nanocarriers.
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Younis, Muhammad, Sana Shaikh, Khawar Ali Shahzad, Fei Tan, Zhao Wang, and Mushtaq Hussain Lashari. "Amrubicin encapsulated PLGA NPs inhibits the PI3K/AKT signaling pathway by activating PTEN and inducing apoptosis in TMZ-resistant Glioma." Biomedical Materials, January 5, 2024. http://dx.doi.org/10.1088/1748-605x/ad1bb2.
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Abstract Glioblastoma (GBM) is an aggressive and deadly brain tumor, and currently, there is no effective cure available for its treatment. Although nanotechnology-based strategies have shown great potential in treating GBM, a major concern is the lack of efficient clearance of these nanoparticles from the body's organs, which limits their translation from laboratory studies to clinical settings. To address this issue, a study was conducted to investigate the potential of using amrubicin (AMR) encapsulated in poly (lactic-co-glycolic acid) nanoparticles (AMR-PLGA-NPs) against temozolomide (TMZ) resistant GBM. The study found that AMR-PLGA-NPs significantly inhibited the cell viability and migration of TMZ-resistant GBM cells. Additionally, the nanoparticles were effective in suppressing the PI3K/AKT signaling pathway, inducing apoptosis in TMZ-resistant glioma cancer cells and glioma stem-like cells (GSCs) by activating PTEN. Furthermore, AMR-PLGA-NPs can pass the biological barrier in in vivo mice model. These findings indicate that AMR-PLGA-NPs can be an effective and flexible nanoplatform for treating GBM while addressing drug resistance issues. Overall, the study demonstrates the potential of AMR-PLGA-NPs as a stable and safe treatment option for GBM, addressing the major issue of drug resistance in these types of tumors.
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Wang, Jingmei, Wenguang Yang, Xinyuan He, Zhang Zhang, and Xiaoqiang Zheng. "Assembling p53 Activating Peptide With CeO2 Nanoparticle to Construct a Metallo-Organic Supermolecule Toward the Synergistic Ferroptosis of Tumor." Frontiers in Bioengineering and Biotechnology 10 (June 28, 2022). http://dx.doi.org/10.3389/fbioe.2022.929536.
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Inducing lipid peroxidation and subsequent ferroptosis in cancer cells provides a potential approach for anticancer therapy. However, the clinical translation of such therapeutic agents is often hampered by ferroptosis resistance and acquired drug tolerance in host cells. Emerging nanoplatform-based cascade engineering and ferroptosis sensitization by p53 provides a viable rescue strategy. Herein, a metallo-organic supramolecular (Nano-PMI@CeO2) toward p53 restoration and subsequent synergistic ferroptosis is constructed, in which the radical generating module-CeO2 nanoparticles act as the core, and p53-activator peptide (PMI)-gold precursor polymer is in situ reduced and assembled on the CeO2 surface as the shell. As expected, Nano-PMI@CeO2 effectively reactivated the p53 signaling pathway in vitro and in vivo, thereby downregulating its downstream gene GPX4. As a result, Nano-PMI@CeO2 significantly inhibited tumor progression in the lung cancer allograft model through p53 restoration and sensitized ferroptosis, while maintaining favorable biosafety. Collectively, this work develops a tumor therapeutic with dual functions of inducing ferroptosis and activating p53, demonstrating a potentially viable therapeutic paradigm for sensitizing ferroptosis via p53 activation. It also suggests that metallo-organic supramolecule holds great promise in transforming nanomedicine and treating human diseases.
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Zhang, Chi, Jingsheng Huang, Ziling Zeng, Shasha He, Penghui Cheng, Jingchao Li, and Kanyi Pu. "Catalytical nano-immunocomplexes for remote-controlled sono-metabolic checkpoint trimodal cancer therapy." Nature Communications 13, no. 1 (June 16, 2022). http://dx.doi.org/10.1038/s41467-022-31044-6.
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AbstractCheckpoint immunotherapies have been combined with other therapeutic modalities to increase patient response rate and improve therapeutic outcome, which however exacerbates immune-related adverse events and requires to be carefully implemented in a narrowed therapeutic window. Strategies for precisely controlled combinational cancer immunotherapy can tackle this issue but remain lacking. We herein report a catalytical nano-immunocomplex for precise and persistent sono-metabolic checkpoint trimodal cancer therapy, whose full activities are only triggered by sono-irradiation in tumor microenvironment (TME). This nano-immunocomplex comprises three FDA-approved components, wherein checkpoint blockade inhibitor (anti-programmed death-ligand 1 antibody), immunometabolic reprogramming enzyme (adenosine deaminase, ADA), and sonosensitizer (hematoporphyrin) are covalently immobilized into one entity via acid-cleavable and singlet oxygen-activatable linkers. Thus, the activities of the nano-immunocomplex are initially silenced, and only under sono-irradiation in the acidic TME, the sonodynamic, checkpoint blockade, and immunometabolic reprogramming activities are remotely awakened. Due to the enzymatic conversion of adenosine to inosine by ADA, the nano-immunocomplex can reduce levels of intratumoral adenosine and inhibit A2A/A2B adenosine receptors-adenosinergic signaling, leading to efficient activation of immune effector cells and inhibition of immune suppressor cells in vivo. Thus, this study presents a generic and translatable nanoplatform towards precision combinational cancer immunotherapy.
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Ding, Cheng, Chuang Yang, Tao Cheng, Xingyan Wang, Qiaojie Wang, Renke He, Shang Sang, et al. "Macrophage-biomimetic porous Se@SiO2 nanocomposites for dual modal immunotherapy against inflammatory osteolysis." Journal of Nanobiotechnology 19, no. 1 (November 22, 2021). http://dx.doi.org/10.1186/s12951-021-01128-4.
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Abstract Background Inflammatory osteolysis, a major complication of total joint replacement surgery, can cause prosthesis failure and necessitate revision surgery. Macrophages are key effector immune cells in inflammatory responses, but excessive M1-polarization of dysfunctional macrophages leads to the secretion of proinflammatory cytokines and severe loss of bone tissue. Here, we report the development of macrophage-biomimetic porous SiO2-coated ultrasmall Se particles (porous Se@SiO2 nanospheres) to manage inflammatory osteolysis. Results Macrophage membrane-coated porous Se@SiO2 nanospheres(M-Se@SiO2) attenuated lipopolysaccharide (LPS)-induced inflammatory osteolysis via a dual-immunomodulatory effect. As macrophage membrane decoys, these nanoparticles reduced endotoxin levels and neutralized proinflammatory cytokines. Moreover, the release of Se could induce macrophage polarization toward the anti-inflammatory M2-phenotype. These effects were mediated via the inhibition of p65, p38, and extracellular signal-regulated kinase (ERK) signaling. Additionally, the immune environment created by M-Se@SiO2 reduced the inhibition of osteogenic differentiation caused by proinflammation cytokines, as confirmed through in vitro and in vivo experiments. Conclusion Our findings suggest that M-Se@SiO2 have an immunomodulatory role in LPS-induced inflammation and bone remodeling, which demonstrates that M-Se@SiO2 are a promising engineered nanoplatform for the treatment of osteolysis occurring after arthroplasty. Graphical Abstract
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Wang, Yi, Tengda Chu, Ting Jin, Shengming Xu, Cheng Zheng, Jianmin Huang, Sisi Li, et al. "Cascade Reactions Catalyzed by Gold Hybrid Nanoparticles Generate CO Gas Against Periodontitis in Diabetes." Advanced Science, April 22, 2024. http://dx.doi.org/10.1002/advs.202308587.
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AbstractThe treatment of diabetic periodontitis poses a significant challenge due to the presence of local inflammation characterized by excessive glucose concentration, bacterial infection, and high oxidative stress. Herein, mesoporous silica nanoparticles (MSN) are embellished with gold nanoparticles (Au NPs) and loaded with manganese carbonyl to prepare a carbon monoxide (CO) enhanced multienzyme cooperative hybrid nanoplatform (MSN‐Au@CO). The Glucose‐like oxidase activity of Au NPs catalyzes the oxidation of glucose to hydrogen peroxide (H2O2) and gluconic acid，and then converts H2O2 to hydroxyl radicals (•OH) by peroxidase‐like activity to destroy bacteria. Moreover, CO production in response to H2O2, together with Au NPs exhibited a synergistic anti‐inflammatory effect in macrophages challenged by lipopolysaccharides. The underlying mechanism can be the induction of nuclear factor erythroid 2‐related factor 2 to reduce reactive oxygen species, and inhibition of nuclear factor kappa‐B signaling to diminish inflammatory response. Importantly, the antibacterial and anti‐inflammation effects of MSN‐Au@CO are validated in diabetic rats with ligature‐induced periodontitis by showing decreased periodontal bone loss with good biocompatibility. To summarize, MSN‐Au@CO is fabricate to utilize glucose‐activated cascade reaction to eliminate bacteria, and synergize with gas therapy to regulate the immune microenvironment, offering a potential direction for the treatment of diabetic periodontitis.
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Zhang, Qi, Shengnan Li, Hua Chen, Jiaqing Yin, Yuqin Chen, Linfeng Liu, Weichong He, et al. "Reduction of Oxidative Stress and Excitotoxicity by Mesenchymal Stem Cell Biomimetic Co‐Delivery System for Cerebral Ischemia‐Reperfusion Injury Treatment." Small, July 2024. http://dx.doi.org/10.1002/smll.202401045.
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AbstractA cerebral ischemia‐reperfusion injury is ensued by an intricate interplay between various pathological processes including excitotoxicity, oxidative stress, inflammation, and apoptosis. For a long time, drug intervention policies targeting a single signaling pathway have failed to achieve the anticipated clinical efficacy in the intricate and dynamic inflammatory environment of the brain. Moreover, inadequate targeted drug delivery remains a significant challenge in cerebral ischemia‐reperfusion injury therapy. In this study, a multifunctional nanoplatform (designated as PB‐006@MSC) is developed using ZL006‐loaded Prussian blue nanoparticles (PBNPs) camouflaged by a mesenchymal stem cell (MSC) membrane (MSCm). ZL006 is a neuroprotectant. It can be loaded efficiently into the free radical scavenger PBNP through mesoporous adsorption. This can simultaneously modulate multiple targets and pathways. MSCm biomimetics can reduce the nanoparticle immunogenicity, efficiently enhance their homing capability to the cerebral ischemic penumbra, and realize active‐targeting therapy for ischemic stroke. In animal experiments, PB‐006@MSC integrated reactive oxygen species (ROS) scavenging and neuroprotection. Thereby, it selectively targeted the cerebral ischemic penumbra (about fourfold higher accumulation at 24 h than in the non‐targeted group), demonstrated a remarkable therapeutic efficacy in reducing the volume of cerebral infarction (from 37.1% to 2.3%), protected the neurogenic functions, and ameliorated the mortality.
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Hu, Jianlun, Xiaofeng Wang, Qi Sun, Shuyang Yang, Min Feng, Tao Zhang, and Hao Hong. "A Polysaccharide Metal Phenolic Network Nanocomposite for Theranostic Applications in Inflammatory Bowel Disease." Advanced Functional Materials, November 22, 2024. http://dx.doi.org/10.1002/adfm.202416918.
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AbstractNanotechnology has significantly facilitated the diagnosis and therapy of inflammatory bowel disease (IBD). To obtain better therapeutic efficacy, a nanoplatform built from polysaccharides and metal‐phenolic networks (MPN) is developed here to enhance retention in the damaged intestinal region and modulate systemic immunological status in IBD models. Polysaccharides from tragacanth gum (GUM) are coordinated with iron and further interact with shikonin (Shik) to obtain a nanocomposite named Shik‐Fe@GUM. Shik‐Fe@GUM demonstrates strong and persistent accumulation in the inflamed intestinal region, which is validated in clinical specimens from IBD patients, cocultured cellular models, and living animals. Shik‐Fe@GUM served as a strong scavenger for reactive oxygen or nitrogen species in inflamed tissues or cells, and alleviated local and systemic inflammatory status by cytokine downregulation. In addition, Shik‐Fe@GUM restored the functions of damaged colonic barriers and mitigate disease activity index. The working mechanisms of Shik‐Fe@GUM are also explored and genetic sequencing results revealed that Shik‐Fe@GUM imposed its treatment effect from attenuating major inflammatory pathways. In particular, Shik‐Fe@GUM can modulate IL‐17RA relevant cell signaling and reduce the recruitment of Th17 cells (T helper cell 17). This polysaccharide‐metal‐functional molecule hybrid strategy can be broadly applicable to other IBD drugs and enhance their therapeutic index in patients.
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Qiao, Han, Jingtian Mei, Kai Yuan, Kai Zhang, Feng Zhou, Tingting Tang, and Jie Zhao. "Immune-regulating strategy against rheumatoid arthritis by inducing tolerogenic dendritic cells with modified zinc peroxide nanoparticles." Journal of Nanobiotechnology 20, no. 1 (July 14, 2022). http://dx.doi.org/10.1186/s12951-022-01536-0.
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AbstractIn hypoxic dendritic cells (DCs), a low level of Zn2+ can induce the activation of immunogenic DCs (igDCs), thereby triggering an active T-cell response to propel the immune progression of rheumatoid arthritis (RA). This finding indicates the crucial roles of zinc and oxygen homeostasis in DCs during the pathogenesis of RA. However, very few studies have focused on the modulation of zinc and oxygen homeostasis in DCs during RA treatment. Proposed herein is a DC-targeting immune-regulating strategy to induce igDCs into tolerogenic DCs (tDCs) and inhibit subsequent T-cell activation, referred to as ZnO2/Catalase@liposome-Mannose nanoparticles (ZnCM NPs). ZnCM NPs displayed targeted intracellular delivery of Zn2+ and O2 towards igDCs in a pH-responsive manner. After inactivating OTUB1 deubiquitination, the ZnCM NPs promoted CCL5 degradation via NF-κB signalling, thereby inducing the igDC-tDC transition to further inhibit CD4+ T-cell homeostasis. In collagen-induced arthritis (CIA) mice, this nanoimmunoplatform showed significant accumulation in the spleen, where immature DCs (imDCs) differentiated into igDCs. Splenic tDCs were induced to alleviate ankle swelling, improve walking posture and safely inhibit ankle/spleen inflammation. Our work pioneers the combination of DC-targeting nanoplatforms with RA treatments and highlights the significance of zinc and oxygen homeostasis for the immunoregulation of RA by inducing tDCs with modified ZnO2 NPs, which provides novel insight into ion homeostasis regulation for the treatment of immune diseases with a larger variety of distinct metal or nonmetal ions. Graphical Abstract
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Qian, Hang, Dong Wang, Binfeng He, Qian Liu, Yu Xu, Di Wu, Chunfa Chen, Wen Zhang, David Tai Leong, and Guansong Wang. "Assembling defined DNA nanostructures with anticancer drugs: a metformin/DNA complex nanoplatform with a synergistic antitumor effect for KRAS-mutated lung cancer therapy." NPG Asia Materials 14, no. 1 (October 7, 2022). http://dx.doi.org/10.1038/s41427-022-00427-y.
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AbstractHerein, a strategy is proposed to simultaneously deliver the small-molecule drug metformin and siRNA with self-assembled DNA nanostructures. The biomedical application of DNA nanostructures is highly promising but still in its infancy. DNA nanostructures as drug delivery vehicles are conventionally synthesized in a magnesium-containing buffer. We propose using an anticancer drug to assemble DNA nanostructures and deliver them with siRNA for synergistic anticancer therapy. The metformin cargo induces DNA self-assembly into well-defined, uniform nanostructures, producing a drug–DNA nanocomplex with multiple functionalities for cancer therapy. Both tile-based and DNA origami structures can be assembled with metformin. The as-prepared metformin/DNA nanocomplex showed high structural and thermal stability and enzymatic resistance in physiological settings. The metformin in the nanocomplex and the KRASG12C siRNA exerted a strong, synergistic antitumor effect against KRAS-mutated non-small cell lung cancer (NSCLC) both in vitro and in vivo by suppressing the RAS/AKT/mTOR and AMPK/AKT/mTOR signaling pathways. The current study suggests that the assembly of complex DNA nanomaterials with carefully chosen small molecules is key to endowing DNA nanostructures with new functionalities and subsequently expanding their applications in multidisciplinary research fields.
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Lee, Sanghee, Sian Lee, Hyojin Lee, Seongchan Kim, and Dong‐Hyun Kim. "Therapeutic Glypican‐3 CRISPR Genome‐Editing Using UltraLarge Porous Silica Nano‐Depot for the Treatment of Hepatocellular Carcinoma." Small Science, November 21, 2024. http://dx.doi.org/10.1002/smsc.202400447.
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Glypican‐3 (GPC3) is a key diagnostic marker and therapeutic target in hepatocellular carcinoma (HCC), interacting with Wnt and Hippo/YAP pathways related to cancer proliferation. Modulating GPC3 gene expression can induce liver cancer cell death by disrupting growth factor signaling, cell adhesion, and metabolic regulation. This study presents the development of a non‐viral ultralarge porous CRISPR‐Cas9 silica nano‐depot to perform targeted GPC3 genome editing for the treatment of HCC. The synthesized ultralarge porous silica nano‐depot (UPSND) encapsulates substantial CRISPR‐Cas9‐ribonucleoprotein complexes with a remarkable 98.3% loading efficiency. The UPSND‐mediated GPC3 CRISPR‐Cas9 therapy significantly suppresses cancer cell proliferation by modulating the Wnt and Hippo/YAP pathways. The efficiency of GPC3 gene deletion is observed to be 5.1‐fold higher than that of commercial lipid‐based GPC3 CRISPR‐Cas9 in both human and murine genes, with minimal off‐target effects. In vivo systemic administration of GPC3 Cas9‐RNP@UPSND resulted in preferential accumulation within hepatic tissues in orthotopic HCC mouse models, leading to complete tumor eradication and enhancing T‐cell tumor‐infiltration. Furthermore, the GPC3 CRISPR‐Cas9@UPSND treatment exhibits superior anti‐proliferative efficacy in tumor‐growth prevention compared to Codrituzumab, as evidenced by the analysis of Ki67 and GPC3 expression, along with serum GPC3 levels. These findings underscore the translational potential of the non‐viral UPSND nanoplatform‐based CRISPR GPC3 genome editing, offering a promising targeted therapeutic strategy for HCC treatment.