bims-engexo 2024-12-01 papers

bims-engexo

Biomed News

on Engineered exosomes

Issue of 2024–12–01
eleven papers selected by
Ravindran Jaganathan, Universiti Kuala Lumpur

Engineered macrophages: an "Intelligent Repair" cellular machine for heart injury.
Significance of exosomes in osteosarcoma research: a systematic review and meta-analysis of a singular clinical investigation.
[Advances in the application of live bacteria as vehicles for delivering antitumor drugs].
Mechanistic paradigms of immunotoxicity, triggered by nanoparticles - a review.
Engineered extracellular vesicles as nanosponges for lysosomal degradation of PCSK9.
Extracellular vesicles originating from the mechanical microenvironment in the pathogenesis and applications for cardiovascular diseases.
Unlocking Genome Editing: Advances and Obstacles in CRISPR/Cas Delivery Technologies.
Exosomes from Limosilactobacillus fermentum Ameliorate Benzalkonium Chloride-Induced Inflammation in Conjunctival Cells.
Stability, challenges, and prospects of chitosan for the delivery of anticancer drugs and tissue regenerative growth factors.
Mesenchymal Stem Cell-Derived Exosomes: Emerging as a Promising Cell-Free Therapeutic Strategy for Autoimmune Hepatitis.
Small and Long Non-Coding RNA Analysis for Human Trophoblast-Derived Extracellular Vesicles and Their Effect on the Transcriptome Profile of Human Neural Progenitor Cells.

Cell Regen. 2024 Nov 27. 13(1): 25

Engineered macrophages: an "Intelligent Repair" cellular machine for heart injury.

Zhuo Zhang, Hetian Du, Weijie Gao, Donghui Zhang.

  Macrophages are crucial in the heart's development, function, and injury. As part of the innate immune system, they act as the first line of defense during cardiac injury and repair. After events such as myocardial infarction or myocarditis, numerous macrophages are recruited to the affected areas of the heart to clear dead cells and facilitate tissue repair. This review summarizes the roles of resident and recruited macrophages in developing cardiovascular diseases. We also describe how macrophage phenotypes dynamically change within the cardiovascular disease microenvironment, exhibiting distinct pro-inflammatory and anti-inflammatory functions. Recent studies reveal the values of targeting macrophages in cardiovascular diseases treatment and the novel bioengineering technologies facilitate engineered macrophages as a promising therapeutic strategy. Engineered macrophages have strong natural tropism and infiltration for cardiovascular diseases aiming to reduce inflammatory response, inhibit excessive fibrosis, restore heart function and promote heart regeneration. We also discuss recent studies highlighting therapeutic strategies and new approaches targeting engineered macrophages, which can aid in heart injury recovery.

Keywords:  Engineered macrophage; Gene editing; Inflammation; Macrophage; Myocardial injury and repair; Targeted delivery

DOI:  https://doi.org/10.1186/s13619-024-00209-7
Front Cell Dev Biol. 2024 ;12 1473044

Significance of exosomes in osteosarcoma research: a systematic review and meta-analysis of a singular clinical investigation.

Xuehong Liu, Jingyao Ye, Wenlong Guo, Junqing Wang.

   Background: Osteosarcoma is the most prevalent among primary bone malignancies, and its standard intervention involves neoadjuvant chemotherapy - surgical adjuvant chemotherapy (MAP regimen) with adriamycin, cisplatin, and high-dose methotrexate. Early-stage osteosarcoma can be effectively treated with surgical resection along with chemotherapy or radiotherapy. However, as the cancer progresses, the efficacy of chemo- and radiotherapy decreases, and the associated problems increase. The current understanding of osteosarcoma development, diagnosis, and treatment does not meet clinical demands. More recently, there has been a significant increase in exosome-associated osteosarcoma research, potentially opening up novel possibilities for osteosarcoma research.
Purpose: We comprehensively evaluated and analyzed the advancement of preclinical research related to exosome-osteosarcoma. We aimed to establish a practical, theoretical foundation for future research initiatives.
Study design: The selected design was a systematic review and meta-analysis.
Methods: Scientific databases, such as PubMed, Embase, The Cochrane Library, and Web of Science, were extensively screened for exosome and osteosarcoma articles. Two highly trained investigators separately reviewed the literature, extracted relevant information, and assessed study quality. Subsequently, we conducted a meta-analysis using Review Manager 5.4.
Results: In total, 25 animal-based randomized controlled trials (RCTs) were selected for analysis. Among them, 13 studies provided strong evidence of cellular exosomes regulating osteosarcoma development from bone marrow mesenchymal stem cells, osteosarcoma cells, and macrophages. In addition, 12 studies demonstrated the therapeutic potential of exosomes in managing osteosarcoma, among which 7 studies transplanted transfected exosomes directly into animals as drugs, and five studies employed exosomes as drug carriers, which were next transplanted into animals.
Conclusion: Based on our meta-analysis, macrophages strongly modulate osteosarcoma development, and engineered exosomes provide the most effective exosome-based osteosarcoma treatment.

Keywords:  chemotherapy; exosomes; meta-analysis; osteosarcoma; preclinical studies

DOI:  https://doi.org/10.3389/fcell.2024.1473044
Sheng Wu Gong Cheng Xue Bao. 2024 Nov 25. 40(11): 3861-3871

[Advances in the application of live bacteria as vehicles for delivering antitumor drugs].

Tingting Hua, Bin Zheng, Yang Bai.

  Some bacteria can selectively colonize the tumor site and inhibit tumor growth, serving as ideal vehicles for delivering antitumor drugs. The system of delivering antitumor drugs with live bacteria as vehicles is characterized by good biocompatibility and precise targeting. However, the development of bacteria as drug delivery vehicles is limited by their own immunogenicity. In this paper, the selection of chassis bacteria, bacterial loading drug strategies, antitumor drug delivery applications and their limitations are elaborated in detail, and its future development direction is envisioned, with a view to providing a reference for the study of live bacteria as antitumor drug delivery carriers.

Keywords:  delivery strategies; drugs; engineered bacteria; live bacteria; tumors

DOI:  https://doi.org/10.13345/j.cjb.240241
Toxicol Mech Methods. 2024 Nov 25. 1-29

Mechanistic paradigms of immunotoxicity, triggered by nanoparticles - a review.

S V S Rana.

  Nanoparticles (NPs) possess the ability to penetrate cells and elicit a rapid and targeted immune response, influenced by their distinct physicochemical properties. These particles can engage with both micro and macromolecules, thereby impacting various downstream signaling pathways that may lead to cell death. This review provides a comprehensive overview of the primary mechanisms contributing to the immunotoxicity of both organic and inorganic nanoparticles. The effects of carbon-based nanomaterials (CNMs), including single-walled carbon nanotubes, multi-walled carbon nanotubes, graphene, and metal oxide nanoparticles, on various immune cell types such as macrophages, neutrophils, monocytes, dendritic cells (DCs), antigen-presenting cells (APCs), and RAW 264.7 cells are examined. The immune responses discussed encompass inflammation, oxidative stress, autophagy, and apoptosis. Additionally, the roles of pro-inflammatory cytokines such as IL-1β, IL-6, TNF-α, and IFN-γ, along with JAK/STAT signaling pathways, are highlighted. The interaction of NPs with oxidative stress pathways, including MAPK signaling and Nrf2/ARE signaling, is also explored. Furthermore, the mechanisms by which nanoparticles induce damage to organelles such as lysosomes, the endoplasmic reticulum, exosomes, and Golgi bodies within the immune system are addressed. The review also emphasizes the genotoxic and epigenetic mechanisms associated with the immunotoxicity of NPs. Recent advancements regarding the immunotherapeutic potential of engineered NPs are reported. The roles of autophagy and apoptosis in the immunotoxicity of NPs merit further investigation. In conclusion, understanding how engineered nanoparticles modulate immune responses may facilitate the prevention and treatment of human diseases, including cancer and autoimmune disorders. The potential development of new vaccines utilizing engineered NPs could pave the way for innovative approaches in the field of immunotherapy.

Keywords:  Carbon based nanomaterials; apoptosis; autophagy; genotoxicity; inflammation; metal oxide nanoparticles; oxidative stress

DOI:  https://doi.org/10.1080/15376516.2024.2431687
Mol Ther. 2024 Nov 26. pii: S1525-0016(24)00761-5. [Epub ahead of print]

Engineered extracellular vesicles as nanosponges for lysosomal degradation of PCSK9.

Chen Wang, Xueying Zhou, Te Bu, Shuang Liang, Zhenzhen Hao, Mi Qu, Yang Liu, Mengying Wei, Changyang Xing, Guodong Yang, Lijun Yuan.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a crucial role in degradation of low-density lipoprotein receptor (LDLR) and PCSK9 inhibition emerges as an attractive strategy for atherosclerosis management. In this study, extracellular vesicles (EVs) were engineered to nanosponges, which could efficiently adsorb and deliver PCSK9 into lysosomes for degradation. Briefly, nanosponges were engineered by modifying EVs with EGF-A/PTGFRN fusion protein (PCSK9 binding domain EGF-A from the mutant LDLR with higher affinity was fused to the C-terminus of Prostaglandin F2 Receptor Negative Regulator). The modification endowed the EVs with hundreds of EGF-A displayed on the surface and thus the capacity to adsorb PCSK9 efficiently. The adsorbed PCSK9 would thus be delivered into lysosomes for degradation when the nanosponges were endocytosed by liver cell, thus releasing endogenous LDLR from degradation. In ApoE-/- mouse model, tail vein injected nanosponges were able to degrade PCSK9, increase LDLR expression, lower LDL-C level, and thus alleviate atherosclerosis. In summary, we here not only develop a novel strategy for PCSK9 inhibition, but also propose a universal method for adsorption and degradation of circulating proteins for disease management.

DOI: https://doi.org/10.1016/j.ymthe.2024.11.034
Regen Ther. 2024 Jun;26 1069-1077

Extracellular vesicles originating from the mechanical microenvironment in the pathogenesis and applications for cardiovascular diseases.

Yu Zeng, Xiaodong Cui, Hong Li, Yanhui Wang, Min Cheng, Xiaoyun Zhang.

  The mechanical microenvironment plays a crucial regulatory role in the growth and development of cells. Mechanical stimuli, including shear, tensile, compression, and extracellular matrix forces, significantly influence cell adhesion, migration, proliferation, differentiation, and various other cellular functions. Extracellular vesicles (EVs) are involved in numerous physiological and pathological processes, with their occurrence and secretion being strictly regulated by the mechanical microenvironment. Recent studies have confirmed that alterations in the mechanical microenvironment are present in cardiovascular diseases, and the components of EVs can respond to changes in mechanical signals, thereby impacting the progression of these diseases. Additionally, engineered EVs, created by leveraging mechanical microenvironments, can serve as natural drug-delivery vehicles for treating and managing specific diseases. This article systematically reviews the regulatory mechanisms through which the mechanical microenvironment influences EVs and summarizes the role and advancements of EVs derived from this environment in the context of cardiovascular diseases.

Keywords:  Cardiovascular disease; Extracellular vesicles; Mechanical microenvironment; Pressure; Shear stress

DOI:  https://doi.org/10.1016/j.reth.2024.10.012
J Funct Biomater. 2024 Oct 31. pii: 324. [Epub ahead of print]15(11):

Unlocking Genome Editing: Advances and Obstacles in CRISPR/Cas Delivery Technologies.

Bibifatima Kaupbayeva, Andrey Tsoy, Yuliya Safarova Yantsen, Ainetta Nurmagambetova, Hironobu Murata, Krzysztof Matyjaszewski, Sholpan Askarova.

  CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats associated with protein 9) was first identified as a component of the bacterial adaptive immune system and subsequently engineered into a genome-editing tool. The key breakthrough in this field came with the realization that CRISPR/Cas9 could be used in mammalian cells to enable transformative genetic editing. This technology has since become a vital tool for various genetic manipulations, including gene knockouts, knock-in point mutations, and gene regulation at both transcriptional and post-transcriptional levels. CRISPR/Cas9 holds great potential in human medicine, particularly for curing genetic disorders. However, despite significant innovation and advancement in genome editing, the technology still possesses critical limitations, such as off-target effects, immunogenicity issues, ethical considerations, regulatory hurdles, and the need for efficient delivery methods. To overcome these obstacles, efforts have focused on creating more accurate and reliable Cas9 nucleases and exploring innovative delivery methods. Recently, functional biomaterials and synthetic carriers have shown great potential as effective delivery vehicles for CRISPR/Cas9 components. In this review, we attempt to provide a comprehensive survey of the existing CRISPR-Cas9 delivery strategies, including viral delivery, biomaterials-based delivery, synthetic carriers, and physical delivery techniques. We underscore the urgent need for effective delivery systems to fully unlock the power of CRISPR/Cas9 technology and realize a seamless transition from benchtop research to clinical applications.

Keywords:  CRISPR/Cas9; cell-penetrating peptides; delivery strategies; functional biomaterials; genome editing; lipid nanoparticles; synthetic polymers

DOI:  https://doi.org/10.3390/jfb15110324
Int J Mol Sci. 2024 Nov 15. pii: 12282. [Epub ahead of print]25(22):

Exosomes from Limosilactobacillus fermentum Ameliorate Benzalkonium Chloride-Induced Inflammation in Conjunctival Cells.

Kippeum Lee, Hyeonjun Gwon, Joo Yun Kim, Jae Jung Shim, Jae Hwan Lee.

  Dry eye is characterized by persistent instability and decreased tear production, which are accompanied by epithelial lesions and inflammation on the surface of the eye. In our previous paper, we reported that supplementation with Limosilactobacillus fermentum HY7302 (HY7302) could inhibit corneal damage in a benzalkonium chloride (BAC)-induced mouse model of dry eye, through its effects in gut microbiome regulation. The aim of this study was to determine what functional extracellular substances can alter the inflammatory response of conjunctival cells. We isolated exosomes from HY7302 probiotic culture supernatant, analyzed their morphological characteristics, and found that their average size was 143.8 ± 1.1 nm, which was smaller than the exosomes from the L. fermentum KCTC 3112 strain. In addition, HY7302-derived exosomes significantly reduced the levels of genes encoding pro-inflammatory cytokines, including interleukin (IL)-20, IL-8, IL-6, and IL-1B, in BAC-treated human conjunctival cells. Moreover, HY7302-derived exosomes significantly increased the levels of genes encoding tight junction proteins, including TJP1, TJP2, and occludin-1, in Caco-2 cells. Lastly, the HY7302 exosomes reduced mRNA expression levels of IL1B, IL20, IL6, IL8, and NFAT5 in a transwell coculture system. Our findings indicate that HY7302 exosomes have potential for use in the treatment of ocular inflammation-related dry eye disease, through gut-eye axis communication via exosomes.

Keywords:  Limosilactobacillus fermentum HY7302; conjunctiva cell; exosomes; ocular inflammation

DOI:  https://doi.org/10.3390/ijms252212282
Heliyon. 2024 Nov 15. 10(21): e39879

Stability, challenges, and prospects of chitosan for the delivery of anticancer drugs and tissue regenerative growth factors.

Md Hasinur Rahman, Md Ibrahim H Mondal.

  Chitosan, a biopolymer derived from chitin, offers significant potential for regulated anticancer drug administration and tissue regeneration growth factors, owing to its biocompatibility, low toxicity, biodegradability, and little immunogenicity. Moreover, its structure can be extensively modified, for example, to create scaffolds, hydrogels, nanoparticles, and membranes, allowing it to be engineered precisely to achieve specific outcomes However, the therapeutic utilisation of chitosan is impeded by significant challenges, such as its inadequate hemocompatibility, durability, and uniformity in commercial manufacturing. Additionally, there is insufficient research offering a thorough examination of the capabilities, limitations, and challenges related to chitosan as carriers for anticancer drugs and growth factors. This article examines the stability, challenges, and advanced application of chitosan as a drug carrier in anti-cancer therapy and growth factor delivery. The problems of unregulated chitosan degradation arising from unsuitable storage conditions are considered and potential solutions, and areas for future research, are proposed to deal with such problems. Consequently, this review is expected to be highly valuable for aspiring scientists studying chitosan-related systems for delivery of anti-cancer drugs and growth factors.

Keywords:  Anti-cancer drugs; Chitosan; Drug delivery; Growth factors; Stability; Tissue regeneration

DOI:  https://doi.org/10.1016/j.heliyon.2024.e39879
Biomolecules. 2024 Oct 24. pii: 1353. [Epub ahead of print]14(11):

Mesenchymal Stem Cell-Derived Exosomes: Emerging as a Promising Cell-Free Therapeutic Strategy for Autoimmune Hepatitis.

Liwen Wu, Longze Zhang, Minglei Huang, Yan Wu, Sikan Jin, Yaqi Zhang, Xinyun Gan, Ting Yu, Guang Yu, Jidong Zhang, Xianyao Wang.

  Autoimmune hepatitis (AIH) is an immune-mediated liver disease that currently faces limited treatment options. In its advanced stages, AIH can progress to liver fibrosis and cirrhosis. Recent research has increasingly focused on cell-free therapies, particularly the use of mesenchymal stem cell (MSC)-derived exosomes (Exos), which have shown promise in treating autoimmune diseases, including AIH. MSC-Exos, as microvesicles with low immunogenicity, high safety, and permeability, can deliver RNA, DNA, proteins, lipids, and various drugs for disease treatment, showing promising clinical application prospects. This review provides a comprehensive summary of the current research on MSC-Exos in the treatment of autoimmune hepatitis (AIH) and explores the underlying molecular mechanisms involved. It highlights the significant regulatory effects of MSC-Exos on immune cells and their ability to modify the microenvironment, demonstrating anti-inflammatory and anti-fibrotic properties while promoting liver regeneration. Additionally, this review also discusses potential challenges and future strategies for advancing Exo-based therapies in the treatment of AIH.

Keywords:  autoimmune hepatitis; cell-free therapy; exosomes; immunomodulation; mesenchymal stem cells; targeted delivery

DOI:  https://doi.org/10.3390/biom14111353
Cells. 2024 Nov 11. pii: 1867. [Epub ahead of print]13(22):

Small and Long Non-Coding RNA Analysis for Human Trophoblast-Derived Extracellular Vesicles and Their Effect on the Transcriptome Profile of Human Neural Progenitor Cells.

Jessica A Kinkade, Pallav Singh, Mohit Verma, Teka Khan, Toshihiko Ezashi, Nathan J Bivens, R Michael Roberts, Trupti Joshi, Cheryl S Rosenfeld.

  In mice, the fetal brain is dependent upon the placenta for factors that guide its early development. This linkage between the two organs has given rise to the term, the placenta-brain axis. A similar interrelationship between the two organs may exist in humans. We hypothesize that extracellular vesicles (EVs) released from placental trophoblast (TB) cells transport small RNA and other informational biomolecules from the placenta to the brain where their contents have pleiotropic effects. Here, EVs were isolated from the medium in which human trophoblasts (TBs) had been differentiated in vitro from induced pluripotent stem cells (iPSC) and from cultured iPSC themselves, and their small RNA content analyzed by bulk RNA-seq. EVs derived from human TB cells possess unique profiles of miRs, including hsa-miR-0149-3p, hsa-302a-5p, and many long non-coding RNAs (lncRNAs) relative to EVs isolated from parental iPSC. These miRs and their mRNA targets are enriched in neural tissue. Human neural progenitor cells (NPCs), generated from the same iPSC, were exposed to EVs from either TB or iPSC controls. Both sets of EVs were readily internalized. EVs from TB cells upregulate several transcripts in NPCs associated with forebrain formation and neurogenesis; those from control iPSC upregulated a transcriptional phenotype that resembled glial cells more closely than neurons. These results shed light on the possible workings of the placenta-brain axis. Understanding how the contents of small RNA within TB-derived EVs affect NPCs might yield new insights, possible biomarkers, and potential treatment strategies for neurobehavioral disorders that originate in utero, such as autism spectrum disorders (ASDs).

Keywords:  DOHaD; RNAseq; brain; exosomes; in vitro models; lncRNA; miR; miRNA; placenta; transcripts

DOI:  https://doi.org/10.3390/cells13221867