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Search Results (321)

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14 pages, 6164 KB  
Communication
The SGLT2 Inhibitor Dapagliflozin Disrupts the Cell Cycle at High Concentrations Without Altering Glycosphingolipid (De Novo)Biosynthesis
by Richard Jennemann and Roger Sandhoff
Int. J. Mol. Sci. 2025, 26(19), 9811; https://doi.org/10.3390/ijms26199811 - 9 Oct 2025
Abstract
Modern computational screening methods are valuable tools for repurposing approved drugs for novel therapeutic applications. They provide initial insights into alternative uses and may significantly shorten the lengthy process of drug development and regulatory approval. Treatment options for glycosphingolipidoses, lysosomal storage diseases involving [...] Read more.
Modern computational screening methods are valuable tools for repurposing approved drugs for novel therapeutic applications. They provide initial insights into alternative uses and may significantly shorten the lengthy process of drug development and regulatory approval. Treatment options for glycosphingolipidoses, lysosomal storage diseases involving glycosphingolipids (GSLs), are currently limited to a few drugs that inhibit de novo GSL biosynthesis, such as eliglustat and miglustat (Zavesca®). In the search for alternative drugs, dapagliflozin emerged as a promising candidate for off-target therapy. In the present study, we investigated whether dapagliflozin can indeed inhibit GSL synthesis, as predicted by previous computational analyses, and compared its effects with those of the glycosphingolipid synthesis inhibitor, the eliglustat analog Genz-123346, in murine 3T3 and Hepa 1-6 cell lines. While Genz-123346 significantly inhibited glycosphingolipid biosynthesis at concentrations as low as 1 µM, dapagliflozin, even up to 50 µM, had no effect on biosynthesis or de novo biosynthesis in either cell line. These results indicate that dapagliflozin, although assessing effects on the cell cycle, including proliferation at high concentrations, is not a suitable candidate for treating glycosphingolipid storage diseases by substrate reduction. Full article
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41 pages, 3113 KB  
Review
Flavonoid-Based Combination Therapies and Nano-Formulations: An Emerging Frontier in Breast Cancer Treatment
by Priyanka Uniyal, Ansab Akhtar and Ravi Rawat
Pharmaceuticals 2025, 18(10), 1486; https://doi.org/10.3390/ph18101486 - 2 Oct 2025
Viewed by 524
Abstract
Cancer has remained a major global health challenge, with around 20 million new cases and 9.7 million fatalities recorded each year. Even though there has been recent progress in therapies such as radiotherapy, chemotherapy, immunotherapy, and gene therapy, cancer remains a major treatment [...] Read more.
Cancer has remained a major global health challenge, with around 20 million new cases and 9.7 million fatalities recorded each year. Even though there has been recent progress in therapies such as radiotherapy, chemotherapy, immunotherapy, and gene therapy, cancer remains a major treatment challenge due to late diagnosis and difficulties in therapeutic effectiveness. Flavonoids, a substantial category of naturally occurring polyphenols, have received considerable interest in recent years for their potential involvement in cancer management and prevention, especially concerning breast cancer. These bioactive compounds, abundant in vegetables, fruits, and herbs, exhibit various therapeutic actions, including antioxidant, anti-inflammatory, and antimutagenic effects. The advanced therapeutic potential of flavonoids, when combined with FDA-approved medicines, offers synergistic effects and enhanced clinical results. Additionally, flavonoid-loaded nano-formulations, involving co-delivery systems, are being explored to increase solubility, stability, and bioavailability, enabling targeted delivery to cancer cells while reducing off-target adverse effects. This review examines the role of flavonoids in the prevention and management of breast cancer, focusing on their dietary sources, metabolism, and pharmacokinetic properties. Furthermore, we explore novel strategies, such as combination therapies with FDA-approved drugs and the application of flavonoid-based nanoformulations, which have the potential to enhance therapeutic outcomes. The clinical application of these strategies has the potential to improve breast cancer treatment and create new opportunities for the advancement of flavonoid-based therapies. Full article
(This article belongs to the Section Medicinal Chemistry)
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23 pages, 1707 KB  
Review
Engineered Phage-Guided Nanotherapeutic Systems for Precision Antibacterial Therapy: Hacking Bacterial Resistance Mechanisms
by Bandar Aldhubiab and Rashed M. Almuqbil
Pharmaceutics 2025, 17(10), 1288; https://doi.org/10.3390/pharmaceutics17101288 - 2 Oct 2025
Viewed by 343
Abstract
Antibiotic resistance (ABR) poses a critical global public health challenge necessitating immediate action. Without prompt interventions, infections caused by antibiotic-resistant bacteria could surpass the annual mortality rates of all cancers combined by 2050. Phages are one of the most abundant biological entities on [...] Read more.
Antibiotic resistance (ABR) poses a critical global public health challenge necessitating immediate action. Without prompt interventions, infections caused by antibiotic-resistant bacteria could surpass the annual mortality rates of all cancers combined by 2050. Phages are one of the most abundant biological entities on earth that specifically infect and replicate in bacterial cells and can act as potential alternatives to antibiotics. Nanotechnology provides a favorable solution to overcome various challenges linked with phage therapy. Developments in nanotechnology, including nano-encapsulation, offer solutions to various clinical as well as pharmacological challenges by improving delivery efficacy, ensuring controlled release, and protecting phages from environmental degradation and immune clearance. The synergistic actions of phage-guided targeting and the strong bactericidal potential of engineered nanocapsules (NCs) could effectively eradicate multidrug-resistant (MDR) bacteria while diminishing off-target activities. Potential applications of engineered phage-guided nanotherapeutic systems have already been explored in terms of phage/nanocarrier cocktails, enhanced antibacterial activity, effective treatment of nosocomial infections, wound healing, and disruption of bacterial biofilms. The present review focuses on comprehensively discussing the advances in phage-guided NCs along with their mechanisms in enhancing precision antibacterial therapy. In this regard, numerous in vitro and in vivo study findings have been summarized in this review. Moreover, various approaches to overcome and optimize the pharmacokinetic profiles of phage-guided NCs have been discussed. Full article
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30 pages, 1900 KB  
Review
The Life of MicroRNAs: Biogenesis, Function and Decay in Cancer
by Shuang Ding and Pingping Wang
Biomolecules 2025, 15(10), 1393; https://doi.org/10.3390/biom15101393 - 30 Sep 2025
Viewed by 414
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that play pivotal roles in post-transcriptional gene regulation, influencing development, differentiation, and disease pathogenesis. Since their discovery in 1993, miRNAs have been recognized for their evolutionary conservation and pleiotropic effects, with the 2024 Nobel Prize underscoring their [...] Read more.
MicroRNAs (miRNAs) are small non-coding RNAs that play pivotal roles in post-transcriptional gene regulation, influencing development, differentiation, and disease pathogenesis. Since their discovery in 1993, miRNAs have been recognized for their evolutionary conservation and pleiotropic effects, with the 2024 Nobel Prize underscoring their significance in post-transcriptional regulation via the RNA interference (RNAi) pathway. This review synthesizes the complete life cycle of miRNAs—from transcription and processing to function and decay—emphasizing regulatory mechanisms and their implications in human diseases, particularly cancer. We discuss how epitranscriptomic modifications influence miRNA biogenesis and activity, explore their nuclear and mitochondrial functions, and address emerging challenges in miRNA-based therapeutics, including the expanding small RNA landscape such as tRNA-derived small RNAs (tsRNAs), and Argonaute (AGO)-independent activities. Despite hurdles such as modest multi-target effects, off-target interactions, and delivery challenges, miRNAs remain promising as both biomarkers and therapeutic agents, underscoring the need for sustained research to bridge preclinical insights with clinical applications. Full article
(This article belongs to the Special Issue Molecular Signalling Pathways in Tumorigenesis and Tumor Suppression)
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26 pages, 4285 KB  
Review
Progress in the Application of Marine Polysaccharide Drug Delivery Systems in Tumor Immunotherapy: Multiple Mechanisms and Material Forms
by Mingxue Cha, Shuqiang Yan, Yiping Zhang and Peipei Wang
Mar. Drugs 2025, 23(10), 384; https://doi.org/10.3390/md23100384 - 27 Sep 2025
Viewed by 532
Abstract
Tumor immunotherapy, a revolutionary cancer treatment, is hindered by inadequate immune cell activation, immunosuppressive tumor microenvironment (TME), and off-target toxicities of immunotherapeutics. These bottlenecks necessitate innovative strategies to enhance efficacy and reduce side effects. Marine polysaccharides have garnered significant attention due to their [...] Read more.
Tumor immunotherapy, a revolutionary cancer treatment, is hindered by inadequate immune cell activation, immunosuppressive tumor microenvironment (TME), and off-target toxicities of immunotherapeutics. These bottlenecks necessitate innovative strategies to enhance efficacy and reduce side effects. Marine polysaccharides have garnered significant attention due to their potential to enhance immune cell activity and regulate the tumor microenvironment, among other benefits. Due to their excellent biocompatibility, modifiability, and relatively low cost, polysaccharides are increasingly being explored as materials for drug delivery systems. The development of marine polysaccharide-based drug delivery systems represents an opportunity for advancing tumor immunotherapy. This review focuses on the application of marine polysaccharide drug delivery systems in tumor immunotherapy, exploring the mechanisms underlying the bioactivity of marine polysaccharides, the design of drug delivery systems, and the interactions between these systems and tumor immunotherapy, aiming to provide a framework for advancing marine polysaccharide-based therapeutics, accelerating the clinical translation of effective, safe, and targeted tumor immunotherapy strategies. Full article
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19 pages, 1143 KB  
Review
Advances and Applications of Plant Base Editing Technologies
by Hao Peng, Jiajun Li, Kehui Sun, Huali Tang, Weihong Huang, Xi Li, Surong Wang, Ke Ding, Zhiyang Han, Zhikun Li, Le Xu and Ke Wang
Int. J. Mol. Sci. 2025, 26(19), 9452; https://doi.org/10.3390/ijms26199452 - 27 Sep 2025
Viewed by 381
Abstract
Base editing represents a major breakthrough in the field of genome editing in recent years. By fusing deaminases with the CRISPR/Cas system, it enables precise single-base modifications of DNA. This review systematically summarizes the development of base editing technologies, including cytosine base editors [...] Read more.
Base editing represents a major breakthrough in the field of genome editing in recent years. By fusing deaminases with the CRISPR/Cas system, it enables precise single-base modifications of DNA. This review systematically summarizes the development of base editing technologies, including cytosine base editors (CBEs), adenine base editors (ABEs), and glycosylase base editors (GBEs), with a particular focus on their applications in crop improvement as well as future trends and prospects. We highlight advances in the creation of novel germplasm with enhanced stress resistance and desirable agronomic traits through base editing in rice, wheat, maize, potato, and other crops, particularly for improving herbicide resistance, disease resistance, and grain quality. Furthermore, we analyze factors that influence base editing efficiency, noting that challenges remain, such as PAM sequence constraints, limited base conversion types, off-target effects, narrow editing windows, and efficiency variation. Future efforts should aim to optimize deaminase activity, expand PAM compatibility, and develop versatile tools to facilitate the broad application of base editing in molecular breeding. This review provides a timely reference for researchers and breeders, offering theoretical guidance and practical insights into harnessing base editing for crop genetic improvement. Full article
(This article belongs to the Special Issue Gene Editing for Cereal Crops)
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25 pages, 726 KB  
Review
Anticancer Activity of Snake Venom Against Breast Cancer: A Scoping Review
by Eun-Jin Kim, Jang-Kyung Park, Soo-Hyun Sung and Hyun-Kyung Sung
Toxins 2025, 17(10), 477; https://doi.org/10.3390/toxins17100477 - 25 Sep 2025
Viewed by 481
Abstract
Breast cancer remains a leading cause of cancer-related mortality worldwide, necessitating innovative therapeutic approaches. This scoping review summarizes experimental evidence on the anticancer activity of snake venom and its bioactive components against breast cancer, drawing from a variety of in vitro and in [...] Read more.
Breast cancer remains a leading cause of cancer-related mortality worldwide, necessitating innovative therapeutic approaches. This scoping review summarizes experimental evidence on the anticancer activity of snake venom and its bioactive components against breast cancer, drawing from a variety of in vitro and in vivo studies. Aimed at critically evaluating the therapeutic potential and underlying mechanisms, this review consolidates findings on venoms from multiple snake species, including both crude preparations and purified proteins or peptides, revealing a diversity of mechanisms of action. Reported effects include induction of apoptosis, generation of reactive oxygen species, disruption of cell membrane integrity, inhibition of cell proliferation and metastasis, and modulation of oncogenic signaling pathways. In vivo findings further indicate tumor growth inhibition and, in some cases, enhanced efficacy when venom-based agents are combined with nanoparticle delivery systems or conventional anticancer drugs. However, a significant proportion of evidence is limited to in vitro studies, with substantial heterogeneity in venom sources, extraction methods, dosages, and cancer models, which constrains generalizability. There is also a lack of systematic data on long-term toxicity, immunogenicity, off-target effects, pharmacokinetics, and formulation challenges. Taken together, these findings highlight snake venom-derived compounds as promising multi-targeted anticancer agents but underscore the urgent need for standardized formulations, rigorous preclinical safety assessments, and translational research to bridge the gap to clinical application. Future investigations should aim to isolate novel venom-derived compounds, refine delivery strategies, and undertake rigorous preclinical safety and pharmacokinetic studies—ultimately moving toward early-phase clinical evaluation to bridge the translational gap and assess the therapeutic potential of these agents. Full article
(This article belongs to the Special Issue Biochemistry, Pathology and Applications of Venoms)
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20 pages, 929 KB  
Review
Genome Editing by Grafting
by Samuel Simoni, Marco Fambrini, Claudio Pugliesi and Ugo Rogo
Int. J. Mol. Sci. 2025, 26(19), 9294; https://doi.org/10.3390/ijms26199294 - 23 Sep 2025
Viewed by 473
Abstract
Grafting is the process of joining parts of two plants, allowing the exchange of molecules such as small RNAs (including microRNAs and small interfering RNAs), messenger RNAs, and proteins between the rootstock and the scion. Genome editing by grafting exploits RNAs, such as [...] Read more.
Grafting is the process of joining parts of two plants, allowing the exchange of molecules such as small RNAs (including microRNAs and small interfering RNAs), messenger RNAs, and proteins between the rootstock and the scion. Genome editing by grafting exploits RNAs, such as tRNA-like sequences (TLS motifs), to deliver the components (RNA) of the clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (Cas9) system from transgenic rootstock to wild-type scion. The complex Cas9 protein and sgRNA-TLS produced in the scion perform the desired modification without the integration of foreign DNA in the plant genome, resulting in heritable transgene-free genome editing. In this review, we examine the current state of the art of this innovation and how it helps address regulatory problems, improves crop recovery and selection, exceeds the usage of viral vectors, and may reduce potential off-target effects. We also discuss the promise of genome editing by grafting for plants recalcitrant to in vitro culture and for agamic-propagated species that must maintain heterozygosity for plant productivity, fruit quality, and adaptation. Furthermore, we explore the limitations of this technique, including variable efficiency, graft incompatibility among genotypes, and challenges in large-scale application, while highlighting its considerable potential for further improvement and future broader applications for crop breeding. Full article
(This article belongs to the Section Molecular Genetics and Genomics)
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18 pages, 871 KB  
Review
Allogeneic NKG2D CAR-T Cell Therapy: A Promising Approach for Treating Solid Tumors
by Sabir A. Mukhametshin, Elvina M. Gilyazova, Damir R. Davletshin, Irina A. Ganeeva, Ekaterina A. Zmievskaya, Vitaly V. Chasov, Alexsei V. Petukhov, Aigul Kh. Valiullina, Sheila Spada and Emil R. Bulatov
Biomedicines 2025, 13(9), 2314; https://doi.org/10.3390/biomedicines13092314 - 22 Sep 2025
Viewed by 687
Abstract
Chimeric Antigen Receptor (CAR)-T cell therapy has transformed the treatment landscape of cancer, yet major challenges remain in enhancing efficacy, reducing adverse effects, and expanding accessibility. Autologous CAR-T cells, derived from individual patients, have achieved remarkable clinical success in hematologic malignancies; however, their [...] Read more.
Chimeric Antigen Receptor (CAR)-T cell therapy has transformed the treatment landscape of cancer, yet major challenges remain in enhancing efficacy, reducing adverse effects, and expanding accessibility. Autologous CAR-T cells, derived from individual patients, have achieved remarkable clinical success in hematologic malignancies; however, their highly personalized nature limits scalability, increases costs, and delays timely treatment. Allogeneic CAR-T cells generated from healthy donors provide an “off-the-shelf” alternative but face two critical immune barriers: graft-versus-host disease (GvHD), caused by donor T-cell receptor (TCR) recognition of host tissues, and host-versus-graft rejection, mediated by recipient immune responses against donor HLA molecules. Recent advances in genome engineering, particularly Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9, allow precise modification of donor T cells to overcome these limitations. For example, TRAC gene knockout eliminates TCR expression, preventing GvHD, while disruption of HLA molecules reduces immunogenicity without impairing cytotoxicity. Beyond hematologic cancers, CRISPR-edited allogeneic CAR-T cells targeting the NKG2D receptor have shown promise in preclinical studies and early-phase trials. NKG2D CAR-T cells recognize stress ligands (MICA/B, ULBP1–6) expressed on over 80% of diverse solid tumors, including pancreatic and ovarian cancers, thereby broadening therapeutic applicability. Nevertheless, the genomic editing process carries risks of off-target effects, including potential disruption of tumor suppressor genes and oncogenes, underscoring the need for stringent safety and quality control. This review examines the distinguishing features of allogeneic versus autologous CAR-T therapy, with a particular focus on NKG2D-based allogeneic CAR-T approaches for solid tumors. We summarize current strategies to mitigate immune barriers, discuss practical manufacturing challenges, and analyze available clinical data on NKG2D CAR-T trials. Collectively, these insights underscore both the promise and the hurdles of developing safe, universal, and scalable allogeneic CAR-T therapies for solid malignancies. Full article
(This article belongs to the Special Issue Novel Progress in Cancer Immunotherapy)
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36 pages, 2272 KB  
Review
Bio-Functional Nanomaterials for Enhanced Lung Cancer Therapy: The Synergistic Roles of Vitamins D and K
by Andreea Crintea, Camelia Munteanu, Tamás Ilyés, Ciprian N. Silaghi and Alexandra M. Crăciun
J. Funct. Biomater. 2025, 16(9), 352; https://doi.org/10.3390/jfb16090352 - 19 Sep 2025
Viewed by 656
Abstract
Lung cancer remains a leading cause of cancer-related mortality worldwide, requiring the development of innovative and effective therapeutic strategies. Bio-functional nanomaterials, due to their unique physicochemical properties, offer a versatile platform for targeted drug delivery, controlled release, and multimodal therapies, thereby enhancing efficacy [...] Read more.
Lung cancer remains a leading cause of cancer-related mortality worldwide, requiring the development of innovative and effective therapeutic strategies. Bio-functional nanomaterials, due to their unique physicochemical properties, offer a versatile platform for targeted drug delivery, controlled release, and multimodal therapies, thereby enhancing efficacy and reducing the systemic toxicity of conventional treatments. Independently, both vitamin D and vitamin K have demonstrated significant anti-cancer properties, including inhibition of proliferation, induction of apoptosis, modulation of angiogenesis, and attenuation of metastatic potential in various cancer cell lines and in vivo models. However, their clinical application is often limited by poor bioavailability, rapid metabolism, and potential for off-target effects. Specifically, by enhancing the solubility, stability, and targeted accumulation of fat-soluble vitamins D and K within tumoral tissues for improved lung cancer therapy, this review emphasizes the novel and cooperative role of bio-functional nanomaterials in overcoming these limitations. Future studies should focus on the logical development of sophisticated nanomaterial carriers for optimal co-delivery plans and thorough in vivo validation, aiming to convert these encouraging preclinical results into successful clinical treatments for patients with lung cancer. Full article
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13 pages, 1571 KB  
Article
CREPE (CREate Primers and Evaluate): A Computational Tool for Large-Scale Primer Design and Specificity Analysis
by Jonathan W. Pitsch, Sara A. Wirth, Nicole T. Costantino, Josh Mejia, Rose M. Doss, Ava V. A. Warren, Jack Ustanik, Xiaoxu Yang and Martin W. Breuss
Genes 2025, 16(9), 1062; https://doi.org/10.3390/genes16091062 - 10 Sep 2025
Viewed by 427
Abstract
Background/Objectives: Polymerase chain reaction (PCR) is ubiquitous in biological research labs, as it is a fast, flexible, and cost-effective technique to amplify a DNA region of interest. However, manual primer design can be an error-prone and time-consuming process depending on the number and [...] Read more.
Background/Objectives: Polymerase chain reaction (PCR) is ubiquitous in biological research labs, as it is a fast, flexible, and cost-effective technique to amplify a DNA region of interest. However, manual primer design can be an error-prone and time-consuming process depending on the number and composition of target sites. While Primer3 has emerged as an accessible tool to solve some of these issues, additional computational pipelines are required for appropriate scaling. Moreover, this does not replace the manual confirmation of primer specificity (i.e., the assessment of off-targets). Methods: To overcome the challenges of large-scale primer design, we fused the functionality of Primer3 and In-Silico PCR (ISPCR); this integrated pipeline, CREPE (CREate Primers and Evaluate), performs primer design and specificity analysis through a custom evaluation script for any given number of target sites at scale. Results: CREPE’s final output summarizes the lead forward and reverse primer pair for each target site, a measure of the likelihood of binding to off-targets, and additional information to aid decision-making. We provide this through a customized workflow for targeted amplicon sequencing (TAS) on a 150 bp paired-end Illumina platform. Experimental testing showed successful amplification for more than 90% of primers deemed acceptable by CREPE. Conclusions: We here provide CREPE, a software platform that allows for parallelized primer design for PCR applications and that is optimized for targeted amplicon sequencing. Full article
(This article belongs to the Section Bioinformatics)
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20 pages, 1228 KB  
Review
siRNA Therapeutics for the Treatment of Hereditary Diseases and Other Conditions: A Review
by Alexei Shevelev, Natalia Pozdniakova, Evgenii Generalov and Olga Tarasova
Int. J. Mol. Sci. 2025, 26(17), 8651; https://doi.org/10.3390/ijms26178651 - 5 Sep 2025
Viewed by 1393
Abstract
RNA-based drugs hold significant potential, offering promising new treatments for a wide range of diseases, especially those with a genetic basis. By leveraging RNA interference (RNAi) and other RNA-mediated mechanisms, these therapies can precisely modulate gene expression and address the root causes of [...] Read more.
RNA-based drugs hold significant potential, offering promising new treatments for a wide range of diseases, especially those with a genetic basis. By leveraging RNA interference (RNAi) and other RNA-mediated mechanisms, these therapies can precisely modulate gene expression and address the root causes of genetic defects. RNA-based drugs hold significant potential for treating a range of diseases. However, the transition of these therapies from laboratory research to clinical applications has encountered hurdles. This review explores the composition and outcomes of clinical trials for various modified short RNA drugs. We detail their mechanisms of action, delivery systems—with a focus on lipid nanoparticles and N-acetylgalactosamine (GalNAc) conjugates—and clinical efficacy in treating conditions such as transthyretin (TTR) amyloidosis. Our analysis reveals that while several RNAi-based drugs have achieved clinical approval, a critical unmet need remains: advanced delivery systems capable of precisely targeting diverse tissues, particularly outside the liver. We also underscore the importance of rigorous target validation utilising sophisticated bioinformatics tools and in vitro/in vivo assays to minimise off-target effects and ensure robust therapeutic efficacy. This review proposes a novel framework for optimising RNA drug development, emphasising the crucial interplay between delivery strategies, target specificity, and understanding disease-specific target biology. Full article
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12 pages, 786 KB  
Article
A SHAP-Guided Grouped L1 Regularization Method for CRISPR-Cas9 Off-Target Predictions
by Evmorfia Tentsidou and Haridimos Kondylakis
Algorithms 2025, 18(9), 561; https://doi.org/10.3390/a18090561 - 4 Sep 2025
Viewed by 449
Abstract
CRISPR-Cas9 has emerged as a remarkably powerful gene editing tool and has advanced both research and gene therapy applications. Machine learning models have been developed to predict off-target cleavages. Despite progress, accuracy, stability, and interpretability remain open challenges. Combining predictive modeling with interpretability [...] Read more.
CRISPR-Cas9 has emerged as a remarkably powerful gene editing tool and has advanced both research and gene therapy applications. Machine learning models have been developed to predict off-target cleavages. Despite progress, accuracy, stability, and interpretability remain open challenges. Combining predictive modeling with interpretability can provide valuable insights into model behavior and increase its trustworthiness. This study proposes a group-wise L1 regularization method guided by SHAP values. For the implementation of this method, the CRISPR-M model was used, and SHAP-informed regularization strengths were calculated and applied to features grouped by relevance. Models were trained on HEK293T and evaluated on K562. In addition to the CRISPR-M baseline, three variants were developed: L1-Grouped-Epigenetics, L1-Grouped-Complete, and L1-Uniform-Epigenetics (control). L1-Grouped-Epigenetics, using penalties split by on- and off-target epigenetic factors, moderately improved mean precision, AUPRC, and AUROC relative to the baseline, as well as showing reduced variability in precision and AUPRC across seeds, although its mean recall and F-metrics were slightly lower than those of CRISPR-M. L1-Grouped-Complete achieved the highest mean AUROC and Spearman correlation and presented lower variability than CRISPR-M for recall, F1, and F-beta, despite reduced recall and F-metrics relative to CRISPR-M. Overall, this approach required only minor architectural adjustments, making it adaptable to other models and domains. While results demonstrate potential for enhancing interpretability and robustness without sacrificing predictive performance, further validation across additional datasets is required. Full article
(This article belongs to the Collection Feature Papers in Evolutionary Algorithms and Machine Learning)
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24 pages, 2933 KB  
Article
M344 Suppresses Histone Deacetylase-Associated Phenotypes and Tumor Growth in Neuroblastoma
by Gabrielle L. Brumfield, Kenadie R. Doty, Shelby M. Knoche, Alaina C. Larson, Benjamin D. Gephart, Don W. Coulter and Joyce C. Solheim
Int. J. Mol. Sci. 2025, 26(17), 8494; https://doi.org/10.3390/ijms26178494 - 1 Sep 2025
Viewed by 593
Abstract
Neuroblastoma (NB) is an aggressive pediatric cancer, with high-risk patients facing a five-year survival rate of ~50%. Standard therapies, including surgery, chemotherapy, radiation, and immunotherapy, are associated with significant long-term toxicities and frequent relapse. Histone deacetylase (HDAC) inhibitors have emerged as promising agents [...] Read more.
Neuroblastoma (NB) is an aggressive pediatric cancer, with high-risk patients facing a five-year survival rate of ~50%. Standard therapies, including surgery, chemotherapy, radiation, and immunotherapy, are associated with significant long-term toxicities and frequent relapse. Histone deacetylase (HDAC) inhibitors have emerged as promising agents for cancer therapy, given their role in modulating gene expression and tumor phenotypes. This study evaluated M344 [4-(dimethylamino)-N-(7-(hydroxyamino)-7-oxoheptyl)benzamide], an HDAC inhibitor, for its efficacy and mechanisms of action against NB. Analysis of clinical NB Gene Expression Omnibus data revealed advanced-stage tumors exhibit higher HDAC expression relative to early-stage samples. M344 treatment effectively increased histone acetylation, induced G0/G1 cell cycle arrest, and activated caspase-mediated cell death. Relative to vorinostat, an HDAC inhibitor in clinical use for lymphoma and clinical trials for NB, M344 displayed superior cytostatic, cytotoxic, and migration-inhibitory effects. In vivo, metronomic M344 dosing suppressed tumor growth and extended survival. Combination therapy with M344 and topotecan improved topotecan tolerability, while M344 co-administration with cyclophosphamide reduced tumor rebound post-therapy. In total, M344 demonstrated strong therapeutic potential for NB, offering improved tumor suppression, reduced off-target toxicities, and enhanced control of tumor growth post-therapy. These findings support further investigation of HDAC inhibitors, such as M344, for clinical application in NB treatment. Full article
(This article belongs to the Special Issue Editorial Board Members’ Collection Series: "Enzyme Inhibition")
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15 pages, 784 KB  
Review
Smart Red Blood Cell Carriers: A Nanotechnological Approach to Cancer Drug Delivery
by Ioannis Tsamesidis, Georgios Dryllis, Sotirios P. Fortis, Andreas Sphicas, Vasiliki Konstantinidou, Maria Chatzidimitriou, Stella Mitka, Maria Trapali, Petros Skepastianos, Anastasios G. Kriebardis and Ilias Pessach
Curr. Issues Mol. Biol. 2025, 47(9), 711; https://doi.org/10.3390/cimb47090711 - 1 Sep 2025
Viewed by 841
Abstract
The efficient and targeted delivery of pharmaceutical substances remains a major challenge in modern therapeutics. Traditional drug delivery systems often suffer from limited bioavailability, rapid clearance, and off-target effects. Red blood cells (erythrocytes), due to their long circulation time, biocompatibility, and immune-evasive properties, [...] Read more.
The efficient and targeted delivery of pharmaceutical substances remains a major challenge in modern therapeutics. Traditional drug delivery systems often suffer from limited bioavailability, rapid clearance, and off-target effects. Red blood cells (erythrocytes), due to their long circulation time, biocompatibility, and immune-evasive properties, have emerged as promising carriers in the development of novel nanotechnology-based drug delivery platforms.A comprehensive literature review was conducted, analyzing recent studies on erythrocyte membrane-coated nanoparticles, their interactions with loaded therapeutic agents, and their performance in vitro and in vivo. Special focus was given to applications in chemotherapy, photodynamic therapy (PDT), photothermal therapy (PTT), and immunotherapy. Erythrocyte-based nanocarriers demonstrated improved circulation times, reduced immune clearance, and enhanced targeting capabilities compared to traditional nanoparticles. Encapsulation of nanoparticles within erythrocyte membranes preserved the functional integrity of the carrier while minimizing systemic toxicity. However, challenges such as membrane stability, hemocompatibility, and the potential for nanoparticle-induced hemoglobin dysfunction were identified as areas requiring further research. In conclusion, erythrocyte membrane-coated nanoparticles represent a unique and promising strategy for drug delivery, combining the natural advantages of red blood cells with the versatility of nanotechnology. Full article
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