bims-carter Biomed News
on CAR-T Therapies
Issue of 2025–06–15
twenty-two papers selected by
Luca Bolliger, lxBio
  1. Aging alters the response to CAR T cell therapy.
  2. Novel strategies to overcome tumor immunotherapy resistance using CAR NK cells.
  3. Mechanistic insights into the limited function of CAR-T cells in solid tumors and potential solutions.
  4. From myth to bedside: a scoping review of the applications of the chimeric antigen receptor in rheumatology.
  5. CAR-T cell therapy in older adults with relapsed/refractory LBCL: benefits and challenges.
  6. Application and prospects of genetic engineering in CAR-NK cell therapy.
  7. Treg cell therapy manufacturability: current state of the art, challenges and new opportunities.
  8. Geometric immunosuppression in CAR T-cell treatment: Insights from mathematical modeling.
  9. Pharmacovigilance analysis of secondary primary malignancies and antibiotic interactions in CAR-T cell therapies.
  10. Cryptic antigens flag cancer cells to T cell therapy.
  11. Engineering the next generation of allogeneic CAR cells: iPSCs as a scalable and editable platform.
  12. CliniMACS Prodigy Manufacturing of Switchable, AND-Gate CAR T Cells.
  13. Insights into next-generation immunotherapy designs and tools: molecular mechanisms and therapeutic prospects.
  14. Research trends and hotspots on gut microbiota in rheumatoid arthritis: a bibliometric analysis from 2004 to 2024.
  15. scEVE: a single-cell RNA-seq ensemble clustering algorithm capitalizing on the differences of predictions between multiple clustering methods.
  16. Environmental factors and clinical markers of stress during neonatal transport: a systematic literature review .
  17. Cytotoxic IgG: Mechanisms, functions, and applications.
  18. Using RNA therapeutics to promote healthy aging.
  19. Reference Vector-guided Evolutionary Algorithm for cluster analysis of single-cell transcriptomes.
  20. From Theory to Therapy: Methylene Blue's Emerging Role in the Management of Septic Shock.
  21. Power of Memory: A Natural Killer Cell Perspective.
  22. Recent Breakthroughs in Exosome-Based Drug Delivery: A Comprehensive Review for Cancer Therapy.
  1. Nat Cancer. 2025 Jun 12.
    Aging alters the response to CAR T cell therapy.
      
    DOI:  https://doi.org/10.1038/s43018-025-00983-6
  2. Front Immunol. 2025 ;16 1550652
    Novel strategies to overcome tumor immunotherapy resistance using CAR NK cells.
    Jun-Hui Guo, Ali Afzal, Sadia Ahmad, Ghazala Saeed, Amna Rehman, Umair Ali Khan Saddozai, Lei Liu, Shi-Hao Guo, Xin-Ying Ji, Muhammad Babar Khawar.
      While immunotherapy faces obstacles, the emergence of chimeric antigen receptor (CAR) engineered natural killer (NK) cells is paving new ways and might become a preferred option over CAR T cells very soon. CAR NK introduce diverse cytotoxic mechanisms offering novel strategies to combat tumor immunotherapy resistance. Concurrently, improvements in NK cell homing and gene-edited CAR NK cell therapy offer promising avenues for overcoming challenges in cancer immunotherapy. Our review addresses resistance mechanisms and engineering strategies to enhance CAR NK cell functionality by improving NK cell homing and migration to tumor sites, emphasizing insights from preclinical and clinical studies.
    Keywords:  CAR NK cells; NK cell homing; cancer immunotherapy; immunotherapy resistance; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1550652
  3. Int Immunopharmacol. 2025 Jun 05. pii: S1567-5769(25)01000-8. [Epub ahead of print]161 115010
    Mechanistic insights into the limited function of CAR-T cells in solid tumors and potential solutions.
    Taku Kouro, Tetsuro Sasada, Kohzoh Imai.
      Chimeric antigen receptor T (CAR-T) cell therapy, in which cytotoxic T cells are engineered to directly recognize tumor antigens, has been shown to be highly effective in the treatment of blood cancers such as acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL). However, its application to solid tumors has not been as successful. Investigations have identified several barriers to the efficacy of CAR-T cell therapy in solid tumors; these include difficulties in target antigen selection, a physical barrier to CAR-T cell infiltration, and an immune-inhibitory environment in tumor tissue. In this review, we present a comprehensive overview of the current understanding of the problems underlying CAR-T cell therapy for solid tumors and potential countermeasures.
    Keywords:  CAR-T; Solid tumor; T cell exhaustion; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.intimp.2025.115010
  4. Clin Exp Med. 2025 Jun 06. 25(1): 189
    From myth to bedside: a scoping review of the applications of the chimeric antigen receptor in rheumatology.
    Reumavance Group
       INTRODUCTION: Chimeric antigen receptor (CAR) based therapies are promising in systemic autoimmune rheumatic disease (SARD) according to recent case reports. To establish the state of the art of the applications of CAR therapies in rheumatology, PubMed, EMBASE, Lilacs, as well as clinical trial registries were searched. Any type of original article that reported the use of these therapies in patients with SARD was included. Forty-eight studies were included from databases. Ninety-five ongoing trials were included from clinical trials registries. The most used type of CAR was a CAR-T against CD19, showing good preliminary results. Other targets used were BCMA, PD-1, a modified HLA and citrullinated peptides among others. The use of other cell types such as natural killer and regulatory T cells was also found. CAR-based therapies in rheumatology are in an early stage of development but with promising results. There has been a notable growth in human patients treated with this intervention in the last 2 years. This and other innovative designs will offer a wide range of new therapeutic possibilities. Results of ongoing clinical trials are needed to establish their efficacy and safety in SARD.
    Keywords:  Autoimmunity; CAR-T; Immunotherapy; Lupus
    DOI:  https://doi.org/10.1007/s10238-025-01717-9
  5. J Immunother Cancer. 2025 Jun 05. pii: e009793. [Epub ahead of print]13(6):
    CAR-T cell therapy in older adults with relapsed/refractory LBCL: benefits and challenges.
    Leyla Shune, Matthew J Frigault, Peter A Riedell.
      Patients with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL) have poor prognosis with a high unmet need for efficacious treatment options. Most patients with r/r large B-cell lymphoma (LBCL) are elderly, which adds to the complexity of choosing the appropriate and effective therapy in these patients. Recently approved therapies, such as CD19-targeted chimeric antigen receptor-T cell therapy, have shown improvements in the outcomes of patients with r/r DLBCL. Several real-world studies also support the use of these newer therapies in elderly patients. However, given the frailty, variability in the risk factors in each elderly patient, and the increased susceptibility for adverse events, a comprehensive geriatric assessment and a multidisciplinary approach could be helpful in guiding the management and treatment choices for these vulnerable patients. Individualized care can aid in giving elderly patients with r/r LBCL the best possible outcome with their chosen treatment regimen.
    Keywords:  Chimeric antigen receptor - CAR; Hematologic Malignancies; Lymphoma
    DOI:  https://doi.org/10.1136/jitc-2024-009793
  6. Front Immunol. 2025 ;16 1600411
    Application and prospects of genetic engineering in CAR-NK cell therapy.
    Caidong Hu, Wenhong Lai, Bin Tian, Xi Xu, Shuiling Xie, Wenting Zhong, Huiqiang Kang, Xiaoyun Chen, Hailiang Li, Jingxin Xu, Liping Liu.
      With the rapid advancement of genetic engineering technologies, CAR-NK cell therapy, as an emerging immunotherapeutic approach, has demonstrated significant potential. CAR-NK cells recognize and eliminate tumor cells through chimeric antigen receptors (CARs). Genetic engineering techniques have enhanced the targeting and anti-tumor activity of CAR-NK cells by optimizing key components of the CAR structure, such as signal peptides, single-chain variable fragments (scFvs), linkers, and hinge regions. Additionally, NK cells can be derived from diverse sources, including peripheral blood, umbilical cord blood, stem cells, and NK cell lines, each with its unique advantages and limitations. Although CAR-NK cell therapy has shown promising anti-tumor efficacy in preclinical studies, it still faces numerous challenges. In the future, further optimization of CAR-NK cell design through genetic engineering and overcoming the immunosuppressive tumor microenvironment will be crucial for enhancing its clinical application efficacy. This review will comprehensively discuss the current applications, technical challenges, and future directions of genetic engineering in CAR-NK cell therapy.
    Keywords:  CAR-NK cells; NK cell expansion; genetic engineering; natural killer cells; tumor microenvironment; vectors for CAR expression
    DOI:  https://doi.org/10.3389/fimmu.2025.1600411
  7. Front Immunol. 2025 ;16 1604483
    Treg cell therapy manufacturability: current state of the art, challenges and new opportunities.
    Janelle Stoops, Tara Morton, James Powell, Amanda L Pace, Jeffrey A Bluestone.
      Autologous cell therapy is a revolutionary new paradigm in medicine. Significant advancements in personalized therapeutic treatments with engineered T cells have been seen across the immuno-oncology markets. The global market is expanding as new cell types treat other conditions, like autoimmunity and transplant rejection. Key to the success of these novel cell therapies is manufacturability; ensuring robust processes that can reliably deliver treatments that meet the medical needs. Using the expertise and experience of the current state of Regulatory T cell (Treg) manufacturing at Sonoma Biotherapeutics as a prototypical case, we review manufacturing challenges and opportunities to ensure success.
    Keywords:  CAR (chimeric antigen receptor) T cell therapy; TCR - T cell receptor; Treg - regulatory T cell; autoimmune diseases; cell therapy manufacturing
    DOI:  https://doi.org/10.3389/fimmu.2025.1604483
  8. Comput Biol Med. 2025 Jun 11. pii: S0010-4825(25)00778-4. [Epub ahead of print]194 110427
    Geometric immunosuppression in CAR T-cell treatment: Insights from mathematical modeling.
    Silvia Bordel-Vozmediano, Soukaina Sabir, Lucía Benito-Barca, Bettina Weigelin, Víctor M Pérez-García.
      Chimeric antigen receptor T (CAR T) cell therapy has emerged as a promising treatment for hematological malignancies, offering a targeted approach to cancer treatment. Understanding the complexities of CAR T-cell therapy within solid tumors poses challenges due to the intricate interactions within the tumor microenvironment. Mathematical modeling may serve as a valuable tool to unravel the dynamics of CAR T-cell therapy and improve its effectiveness in solid tumors. This study aimed to investigate the impact of spatial aspects in CAR T therapy of solid tumors, utilizing cellular automata for modeling purposes. Our main objective was to deepen our understanding of treatment effects by analyzing scenarios with different spatial distributions and varying the initial quantities of tumor and CAR T-cells. Tumor geometry significantly influenced treatment efficacy in-silico, with notable differences observed between tumors with block-like arrangements and those with sparse cell distributions, leading to the concept of immune suppression due to geometrical effects. This research delves into the intricate relationship between spatial dynamics and the effectiveness of CAR T therapy in solid tumors, highlighting the relevance of tumor geometry in the outcome of cellular immunotherapy treatments. Our results provide a basis for improving the efficacy of CAR T-cell treatments by combining them with other ones reducing the density of compact tumor areas and thus opening access ways for tumor killing T-cells.
    Keywords:  CAR T-cell; Cellular automata; Immunotherapy; Spatial dynamics; Tumor geometry
    DOI:  https://doi.org/10.1016/j.compbiomed.2025.110427
  9. Ther Adv Drug Saf. 2025 ;16 20420986251340866
    Pharmacovigilance analysis of secondary primary malignancies and antibiotic interactions in CAR-T cell therapies.
    Yun Peng, Yuxuan Song, Jiaxing Lin, Caipeng Qin, Yiqing Du, Tao Xu.
       Background: Chimeric antigen receptor T-cell (CAR-T) cell therapy represents a significant advancement in cancer treatment, offering remarkable responses in certain hematologic malignancies. However, the risk of secondary primary malignancies (SPMs) associated with CAR-T therapy is a growing concern. Recent studies suggest that antibiotics, which are frequently used in CAR-T patients, may influence this risk, yet their effects remain poorly understood.
    Objective: This study aims to systematically evaluate the association between antibiotics and the incidence and timing of SPMs in patients receiving CAR-T cell therapy, using data from the FDA's Adverse Event Reporting System (FAERS) database.
    Design: We analyzed reports from FAERS spanning from Q2 2017 to Q1 2024, focusing on SPMs associated with various CAR-T therapies.
    Methods: A comprehensive signal analysis was conducted to explore the associations between antibiotic usage and specific SPMs for different CAR-T products. In addition, we employed cumulative hazard curves to evaluate the time to onset of SPMs in patients receiving antibiotics versus those who did not.
    Results: We have provided a comprehensive summary of all signals for CAR-T-associated SPMs. In addition, our analysis identified significant variations in the association between antibiotics and SPM incidence depending on the CAR-T therapy administered. Antibiotics were associated with a decreased risk of SPMs in patients treated with anti-CD19 CAR-T therapies, particularly brexucabtagene autoleucel. Conversely, a higher risk of SPMs was observed in association with antibiotics for anti-BCMA therapies, with idecabtagene vicleucel showing a notably elevated risk. Notably, antibiotics were associated with an earlier onset of SPMs across CAR-T therapies, suggesting a possible relationship between antibiotics and the timing of these malignancies. Finally, we explored the underlying biological pathways that may be associated with these observations.
    Conclusion: Antibiotics were associated with both the risk and timing of SPMs in patients undergoing CAR-T cell therapy. This study highlights the need for further research to better understand the complex interactions between antibiotics and CAR-T therapies, as well as the potential implications for clinical management and patient care.
    Keywords:  CAR-T cell therapy; anti-BCMA; anti-CD19; antibiotics; secondary primary malignancies
    DOI:  https://doi.org/10.1177/20420986251340866
  10. Nat Rev Drug Discov. 2025 Jun 09.
    Cryptic antigens flag cancer cells to T cell therapy.
    Katie Kingwell.
      
    DOI:  https://doi.org/10.1038/d41573-025-00099-7
  11. Stem Cell Reports. 2025 May 21. pii: S2213-6711(25)00119-5. [Epub ahead of print] 102515
    Engineering the next generation of allogeneic CAR cells: iPSCs as a scalable and editable platform.
    Ying Fang, Yuning Chen, Yan-Ruide Li.
      Over the past five years, allogeneic off-the-shelf CAR-engineered cell therapies have advanced rapidly. By bypassing the individualized manufacturing, high cost, and eligibility constraints of autologous products, allogeneic platforms, especially those derived from induced pluripotent stem cells (iPSCs), promise broader, faster access for cancer patients. This perspective reviews recent preclinical and clinical milestones, outlining genetic designs, scalable production workflows, and early-phase trial outcomes. We assess safety profiles, antitumor activity, and in vivo persistence, spotlighting innovations like T cell receptor alpha constant (TRAC) knockout, human leukocyte antigen (HLA) camouflage, and interleukin (IL)-15 armoring. Finally, we identify emerging trends and challenges that will shape the future development of allogeneic iPSC-derived CAR therapies.
    Keywords:  CAR; CRISPR; allogeneic cell therapy; cancer; chimeric antigen receptor; clinical trials; iPSC; immunotherapy; induced pluripotent stem cell
    DOI:  https://doi.org/10.1016/j.stemcr.2025.102515
  12. Int J Mol Sci. 2025 May 23. pii: 5024. [Epub ahead of print]26(11):
    CliniMACS Prodigy Manufacturing of Switchable, AND-Gate CAR T Cells.
    Alexandra von Jutrzenka-Trzebiatowski, Rutuja Gupte, Cansu Daglar, Nicole Berndt, Claudia Arndt, Michael Bachmann, Anja Feldmann.
      The Reverse Chimeric Antigen Receptor (RevCAR) system is an adapter CAR T cell technology that allows the precise tuning of T cell activity and, thus, improved safety management. RevCAR T cells recognize and eradicate tumor cells via a bispecific adapter molecule, termed the RevCAR Target Module (RevTM). To further reduce the risk of on-target off-tumor toxicities, Dual-RevCAR T cells can be employed. These cells harbor two different RevCAR constructs, with the signaling domain of either CD3zeta or CD28. Therefore, Dual-RevCAR T cells only exert their full function when both RevCAR constructs are triggered simultaneously upon recognition of two different tumor antigens via RevTMs, enabling a precise AND-gate targeting approach and rendering them highly interesting for clinical application. For this purpose, standardized and reproducible clinical-grade cell manufacturing is required, for which the CliniMACS Prodigy can be used. Here, we present that automated processing of RevCAR and Dual-RevCAR T cells via the CliniMACS Prodigy results in potent expansion, strong transduction, and a favorable phenotype for clinical application. Moreover, obtained cell products were highly functional in a strict RevTM-dependent manner for both monospecific and AND-gate targeting, clearly underlining their high potential for clinical application against various tumor entities.
    Keywords:  CliniMACS Prodigy; RevCAR and Dual-RevCAR system; adapter CAR T cells; tumor therapy
    DOI:  https://doi.org/10.3390/ijms26115024
  13. J Hematol Oncol. 2025 Jun 07. 18(1): 62
    Insights into next-generation immunotherapy designs and tools: molecular mechanisms and therapeutic prospects.
    Hongzhuo Qin, Zhaokai Zhou, Run Shi, Yumiao Mai, Yudi Xu, Fu Peng, Guangyang Cheng, Pengpeng Zhang, Wenjie Chen, Yun Chen, Yajun Chen, Ran Xu, Qiong Lu.
      Immunotherapy has revolutionized the oncology treatment paradigm, and CAR-T cell therapy in particular represents a significant milestone in treating hematological malignancies. Nevertheless, tumor resistance due to target heterogeneity or mutation remains a Gordian knot for immunotherapy. This review elucidates molecular mechanisms and therapeutic potential of next-generation immunotherapeutic tools spanning genetically engineered immune cells, multi-specific antibodies, and cell engagers, emphasizing multi-targeting strategies to enhance personalized immunotherapy efficacy. Development of logic gate modulation-based circuits, adapter-mediated CARs, multi-specific antibodies, and cell engagers could minimize adverse effects while recognizing tumor signals. Ultimately, we highlight gene delivery, gene editing, and other technologies facilitating tailored immunotherapy, and discuss the promising prospects of artificial intelligence in gene-edited immune cells.
    Keywords:  Adapter CAR; Chimeric antigen receptor; Gene delivery; Gene editing; Logic gate; Multi-targets
    DOI:  https://doi.org/10.1186/s13045-025-01701-6
  14. Clin Exp Rheumatol. 2025 Jun 05.
    Research trends and hotspots on gut microbiota in rheumatoid arthritis: a bibliometric analysis from 2004 to 2024.
    Zesen Zheng, Xiaoyang Liu, Youao Zhang, Huihui Zhang, Shixian Chen, Junqing Zhu.
       OBJECTIVES: Rheumatoid arthritis (RA) is an autoimmune condition linked to alterations in the gut microbiota. This study aims to conduct a comprehensive analysis of the literature on gut microbiota and RA over the past 21 years through bibliometric methods, thereby identifying emerging trends and hotspots, and providing insights for the precision treatment of RA.
    METHODS: The authors analysed articles on gut microbiota in RA published from 2004 to 2024 based on the Web of Science Core Collection database. Bibliometric methods employed tools such as CiteSpace, VOSviewer, and COOC to conduct visual analyses of countries, institutions, references, and keywords.
    RESULTS: 1,267 articles from 80 countries led by China and the United States were included. A notable increase in annual publications reflects the growing interest in this field. Simultaneously, contributions and cooperation of institutions in the field are discussed. Furthermore, co-citation and keyword analysis revealed four research hotspots: 1. specific gut microbiota like Prevotella copri modulating immune responses in RA; 2. dietary interventions regulating gut microbiota as therapeutic approaches for RA; 3. high-throughput sequencing technologies enabling microbiome analysis for diagnostic RA; and 4. probiotics and plant-derived bioactive compounds serving as promising adjunctive therapies for RA management.
    CONCLUSIONS: The relationship between RA and gut microbiota has been extensively studied. The hotspot of future research may be to further study the pathological mechanism of gut microbiota in RA and how to improve the symptoms of RA patients through dietary therapy and adjustment of the homeostasis of gut microbiota.
    DOI:  https://doi.org/10.55563/clinexprheumatol/3899sf
  15. NAR Genom Bioinform. 2025 Jun;7(2): lqaf073
    scEVE: a single-cell RNA-seq ensemble clustering algorithm capitalizing on the differences of predictions between multiple clustering methods.
    Yanis Asloudj, Fleur Mougin, Patricia Thébault.
      Single-cell RNA sequencing measures individual cell transcriptomes in a sample. In the past decade, this technology has motivated the development of hundreds of clustering methods. These methods attempt to group cells into populations by leveraging the similarity of their transcriptomes. Because each method relies on specific hypotheses, their predictions can vary drastically. To address this issue, ensemble algorithms detect cell populations by integrating multiple clustering methods, and minimizing the differences of their predictions. While this approach is sensible, it has yet to address some conceptual challenges in single-cell data science; namely, ensemble algorithms have yet to generate clustering results with uncertainty values and multiple resolutions. In this work, we present an original approach to ensemble clustering that addresses these challenges, by describing the differences between clustering results, rather than minimizing them. We present the scEVE algorithm, and we evaluate it on 15 experimental datasets, and up to 1200 synthetic datasets. Our results reveal that scEVE outperforms the state of the art, and addresses both conceptual challenges. We also highlight how biological downstream analyses will benefit from addressing these challenges. We expect that this work will provide an alternative direction for developing single-cell ensemble clustering algorithms.
    DOI:  https://doi.org/10.1093/nargab/lqaf073
  16. BMJ Paediatr Open. 2025 Jun 12. pii: e003568. [Epub ahead of print]9(1):
    Environmental factors and clinical markers of stress during neonatal transport: a systematic literature review .
    Tone Solvik-Olsen, Marit Bekkevold, Fridtjof Heyerdahl, Astri Maria Lang, Jostein S Hagemo, Marius Rehn.
       BACKGROUND: Neonatal transport is an essential component of modern neonatal intensive care globally, providing access to advanced treatment while exposing vulnerable neonates to environmental conditions that may increase the risk of physiological instability.
    OBJECTIVE: To systematically review studies measuring environmental exposures, specifically vibration, sound and temperature fluctuations during neonatal transport and to evaluate their impact on clinical parameters in neonates.
    METHODS: A systematic literature review identified studies reporting environmental factors or clinical data during transport via ground, rotor or fixed-wing air ambulances. The medical databases searched included MEDLINE/PubMed, Embase, the Cochrane database of systematic reviews, Nursing Reference Center Plus, UpToDate and SveMed covering the period from November 2020 to January 2025.
    RESULTS: 15 observational studies, 13 prospective and 2 retrospective covering publications from 1992 to 2025 were included. The studies included data on vibration, sound, ambient temperature and a wide range of clinical parameters such as heart rate and heart rate variability, change in clinical behaviour scales and cortisol in saliva reflecting the neonatal condition. Only four articles reported the effect of environmental factors on neonatal physiology.
    CONCLUSIONS: This review highlights the presence of environmental factors, particularly noise and vibration, during transport and raises concerns about their impact on neonates. Although diverse clinical parameters were documented, the small sample sizes and variability in measurement methods across studies limit the ability to draw definitive conclusions. These observations emphasise the need for standardised monitoring protocols and further research to optimise neonatal transport practices.
    Keywords:  Health services research; Neonatology; Technology
    DOI:  https://doi.org/10.1136/bmjpo-2025-003568
  17. Immunity. 2025 Jun 10. pii: S1074-7613(25)00229-8. [Epub ahead of print]58(6): 1378-1395
    Cytotoxic IgG: Mechanisms, functions, and applications.
    Miriam Wöhner, Falk Nimmerjahn.
      A key feature of immunoglobulin G (IgG) antibodies is their capacity to deplete target cells, which is broadly referred to as antibody-dependent cellular cytotoxicity (ADCC). The capacity to kill target cells has made cytotoxic antibodies the standard of care for many malignant, autoimmune, and infectious diseases. However, cytotoxic antibody activity in therapeutic settings is often limited, and current optimization approaches have only mildly enhanced therapeutic efficacy. In this review, we discuss the highly complex molecular and cellular pathways underlying an ADCC reaction and how these are impacted by the type of target cell, the effector cells, and the tissue environment. We also discuss implications for improving therapies and provide an updated model of cytotoxic IgG activity.
    Keywords:  Fcgamma receptor; autoimmunity; cancer; cytotoxic antibody; immunoglobulin G
    DOI:  https://doi.org/10.1016/j.immuni.2025.05.008
  18. Nat Aging. 2025 Jun 11.
    Using RNA therapeutics to promote healthy aging.
    Shuying Chen, Qian Chen, Xinru You, Zhuoming Zhou, Na Kong, Fabrisia Ambrosio, Yihai Cao, Reza Abdi, Wei Tao.
      Aging is characterized by a gradual decline of cellular and physiological functions over time and an increased risk of different diseases. RNA therapeutics constitute an emerging approach to target the molecular mechanisms of aging and age-related diseases via rational design and have several advantages over traditional drug therapies, including high specificity, low toxicity and the potential for rapid development and production. Here, we discuss the latest developments in RNA therapeutics designed to promote healthy aging, including RNA activation, messenger RNA therapy, RNA interference, antisense oligonucleotides, aptamers and CRISPR-Cas-mediated RNA editing. We also review the latest preclinical and clinical studies of RNA technology for treating age-related diseases, including neurodegenerative, cardiovascular and musculoskeletal diseases. Finally, we discuss the challenges of RNA technology aimed at supporting healthy aging. We anticipate that the fusion of RNA therapeutics and aging biology will have an important effect on the development of new medicines and maximization of their efficacy.
    DOI:  https://doi.org/10.1038/s43587-025-00895-1
  19. Comput Methods Programs Biomed. 2025 Jun 06. pii: S0169-2607(25)00290-1. [Epub ahead of print]269 108873
    Reference Vector-guided Evolutionary Algorithm for cluster analysis of single-cell transcriptomes.
    Fernando M Rodríguez-Bejarano, Miguel A Vega-Rodríguez, Sergio Santander-Jiménez.
       BACKGROUND AND OBJECTIVE: Single-cell RNA-sequencing (scRNA-seq) has revolutionized transcriptomic studies by providing detailed insights into gene expression profiles at the single-cell level. This technology allows researchers to capture expression patterns of thousands of genes across hundreds or thousands of individual cells. Clustering is a crucial step in the analysis of scRNA-seq data, since it enables the identification of distinct cell populations based on their transcriptomic profiles and serves as a foundation for downstream analysis. Given that clustering scRNA-seq data is a challenging task that involves different conflicting objectives, our goal is to tackle it from a multi-objective optimization perspective.
    METHODS: This study proposes a Reference Vector-guided Evolutionary Algorithm for Cluster Analysis of Single-cell Transcriptomes (RVEA-CAST) to address the clustering task as a multi-objective optimization problem. Our approach considers three objectives to optimize: clustering deviation, clustering compactness, and the Davies-Bouldin index. The algorithmic design of RVEA-CAST incorporates three problem-aware mutation operators specifically designed to improve each objective, which are orchestrated under a multi-objective search engine based on the use of reference vectors.
    RESULTS: RVEA-CAST is evaluated on ten real scRNA-seq datasets using standard clustering evaluation metrics, such as Normalized Mutual Information (NMI) and Adjusted Rand Index (ARI). The attained results reveal the improved performance and robustness of the proposed approach compared to other previously proposed methods. Specifically, statistically significant improvements of up to 66.7% and 261.5% were achieved for NMI and ARI, respectively. Furthermore, the analysis of differentially expressed genes in the predicted and real clusters showcased greater agreement of our solutions with actual cell populations, underscoring the biological relevance of our approach.
    CONCLUSIONS: The results highlight that RVEA-CAST is an effective and versatile approach for clustering scRNA-seq data, outperforming existing methods across diverse biological scenarios in both widely used clustering evaluation metrics and biological relevance.
    Keywords:  Cluster analysis; Multi-objective optimization; Reference Vector-guided Evolutionary Algorithm; ScRNA-seq; Single-cell transcriptome
    DOI:  https://doi.org/10.1016/j.cmpb.2025.108873
  20. J Pharm Pract. 2025 Jun 10. 8971900251350554
    From Theory to Therapy: Methylene Blue's Emerging Role in the Management of Septic Shock.
    Brooke A Smith, Rachel Robinson, Amoreena K Most.
      Purpose: Methylene blue was FDA-approved for the treatment of acquired methemoglobinemia. However, it has also shown benefits in other disease states such as β-blocker and calcium channel blocker overdoses, vasoplegia, and ifosfamide-induced encephalopathy. More recently, methylene blue has emerged as a potential catecholamine sparing agent for the treatment of septic shock through inhibition of the nitric oxide pathway, which is responsible for vasodilation. Studies suggest that methylene blue decreases vasopressor requirements for critically ill patients with minimal safety risks. This clinical review aims to review the pharmacology, efficacy, and safety surrounding methylene blue use in patients with septic shock. Summary: Six studies conducted between 2000 and 2024 were identified. In randomized studies, methylene blue appears to be safe and effective in improving hemodynamics in patients with septic shock. This review discusses pharmacology, pharmacotherapy, and primary literature surrounding methylene blue in septic shock. Conclusion: Based on review of the available literature, authors conclude that methylene blue is an appropriate catecholamine-sparing treatment option for patients with septic shock. However, drug-drug interactions should be carefully reviewed before administration due to the risk of serotonin syndrome when combined with other serotonergic agents.
    Keywords:  adverse effects; catecholamine sparing; methylene blue; review; sepsis; septic shock
    DOI:  https://doi.org/10.1177/08971900251350554
  21. Cells. 2025 Jun 05. pii: 846. [Epub ahead of print]14(11):
    Power of Memory: A Natural Killer Cell Perspective.
    Oishi Sinha, S K Abhipsha, Sumit Sen Santara.
      Memory is an incredible aspect of our immune system. Similarly to our cognitive memory, it allows us to remember and respond more efficiently to subsequent encounters with the same pathogens, making it possible to act on the information built by previous experiences. This process is critical for the body's defenses against infections and is the cornerstone for the effectiveness of vaccines. Immunological memory, traditionally considered an exclusive quality of the adaptive immune system, is a sophisticated component of the immune response system that is characterized by the ability to recognize and remember specific pathogens. This form of memory is primarily observed in antigen-specific T and B cells, which are specialized for recognizing particular antigens and generating a quicker immune response upon each successive reinfection over a long period of time. Natural killer (NK) cells, essential as the body's first line of defense against a wide range of viral infections and tumors, have traditionally been classified as a key component of the innate immune system, characterized by their lack of antigen specificity and memory. However, the concept of innate vs. adaptive has been evolving, with increasing evidence suggesting that specific cellular subsets of the innate immune system may also play a role in immunological memory. This review aims to provide a comprehensive overview of the recent advances in the understandings of the molecular mechanisms driving the development of memory-like properties in NK cells, with a primary focus on human data in the context of various diseases and infectious conditions. Additionally, we will examine the therapeutic implications of these findings, highlighting how insights into NK cell memory can contribute to the development of novel immunotherapies and improve strategies for treating infections, cancer, and autoimmune disorders.
    Keywords:  NK cell-based therapies; NK memory; cancer; cytokine-induced memory-like (CIML); cytomegalovirus (CMV); leukemia; natural killer (NK) cells; tumor-induced memory-like (TIML)
    DOI:  https://doi.org/10.3390/cells14110846
  22. Cancer Biother Radiopharm. 2025 Jun 12.
    Recent Breakthroughs in Exosome-Based Drug Delivery: A Comprehensive Review for Cancer Therapy.
    Dhwani Shah, Shweta Gandhi, Shreeraj Shah, Kaushika Patel.
      Recently, exosomes, or "natural nanoparticles," have been considered as potential drug delivery methods. Due to exosome carriers' natural properties, exosome-mediated drug delivery systems (DDSs) are efficient cancer treatments. Exosomes, small membrane vesicles from many cell types, can transfer phytoconstituents, proteins, nucleic acids, and small molecule medicines across biological boundaries. Recent DDS advances have improved this potential using plant-derived exosomes (PDEs), which are biocompatible and low toxic. PDEs have anticancer effects, especially in the context of conventional treatment resistance, untargeted toxicity, and response variability. This review fills a gap by discussing the latest findings and offering new perspectives on exosome drug delivery in cancer. The study summarizes isolation and loading approaches such as ultracentrifugation and immunological isolation and the characterization parameters for the formulation of exosomes. The exosome-based DDSs are discussed in depth, along with the emphasis on PDEs. The article highlights emerging trends and challenges, including molecular targets and ongoing clinical trials, during the past decade that are critically relevant to the current scenario. Nanotechnology and personalized medicine could improve and lower the cost of exosome-mediated cancer treatment. While the preclinical data have been encouraging, clinical applications of exosome-based therapies are continuing to evolve in its early stages, and some of the problems include scalability, purification, and regulatory compliance.
    Keywords:  bioavailability; cancer; cargo loading; extracellular vesicles; nano drug delivery; plant-derived exosomes
    DOI:  https://doi.org/10.1089/cbr.2025.0050
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