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Myocardial Infarction (MI) leads to the irreversible loss of cardiomyocytes and adverse remodeling, eventually progressing to heart failure (HF). Although gene- and RNA-based therapies offer promising strategies for cardiac repair, current approaches often rely on invasive intramyocardial delivery or are limited by the short duration of expression and low protein yield of traditional mRNA.Consequently, developing a minimally invasive therapeutic platform capable of sustained expression of cardioprotective factors remains a critical unmet need in the field of cardiac therapy.Recently, Professor Ke Cheng's team at Columbia University published a research paper titled "Single intramuscular injection of self-amplifying RNA of Nppa to treat myocardial infarction" in the prestigious international journal Science. The study developed a lipid nanoparticle-delivered self-amplifying RNA therapy (saNppa-LNP). A single intramuscular injection can achieve sustained expression of cardioprotective factors in vivo, significantly improving cardiac function and ventricular remodeling after myocardial infarction, supporting the broader potential of saRNA-LNP-based therapies for treating cardiac diseases.Atrial Natriuretic Peptide (ANP), encoded by the Nppa gene, is a developmentally regulated cardiac hormone with potent cardioprotective functions. The research team previously observed that Nppa expression is induced following myocardial infarction in both neonatal and adult mice; however, the level of induction is significantly higher in the hearts of neonatal mice, which possess strong regenerative capabilities. This disparity suggests that elevated Nppa expression levels may be linked to enhanced cardiac regeneration, whereas the limited repair capacity of adult mouse hearts may be due to insufficient Nppa induction.To address this, the team developed a self-amplifying RNA (saRNA) therapy delivered via lipid nanoparticles (LNPs) to drive additional Nppa expression. Unlike conventional mRNA, saRNA can self-replicate within cells, enabling more persistent protein expression at extremely low doses.Cat.No.Product NamePricePMSAR-0001EGFP saRNAInquiryPMSAR-0002Firefly Luciferase saRNAInquiryPMSAR-0003Nano Luciferase saRNAInquiryPMSAR-0004NLuc-EGFP saRNAInquiryPMSAR-0005Gaussia Luciferase saRNAInquiryPMSAR-0006Renilla Luciferase saRNAInquiryPMSAR-0007mCherry saRNAInquiryPMSAR-0008β-galactosidase saRNAInquiryPMSAR-0009Luciferase P2A GFP saRNAInquiryPMSAR-0010Cas9 saRNAInquiryPMSAR-0011NLS-Cre saRNAInquiryPMSAR-0012Cas9 Nickase saRNAInquiryPMSAR-0013Cas9-T2A-EGFP saRNAInquiryPMSAR-0014Cre-T2A-EGFP saRNAInquiryPMSAR-0015OVA saRNAInquiryThe research team reasoned that a single intramuscular injection of saRNA-LNP encoding native Nppa (saNppa-LNP) could establish an "RNA factory" in the body. This factory continuously produces and secretes Pro-ANP, a precursor that enters the circulatory system. Pro-ANP is then selectively cleaved and activated into functional ANP by Corin—a cardiac protease highly expressed only in the heart. This achieves a "muscle production, cardiac activation" model, providing long-lasting cardioprotection without the need for direct cardiac intervention.Experimental results showed that a single intramuscular injection of saNppa-LNP in mice induced robust Pro-ANP secretion lasting for at least four weeks, outperforming an equivalent dose of mRNA-LNP. In mouse models of acute myocardial infarction and ischemia/reperfusion (I/R) injury, saNppa-LNP treatment significantly increased left ventricular ejection fraction (LVEF), reduced infarct size, and mitigated fibrosis. These therapeutic benefits were consistently validated in aged, atherosclerotic, and diabetic myocardial infarction models. Furthermore, large animal studies in a porcine I/R model confirmed that a single intramuscular injection effectively protected cardiac function and limited adverse cardiomyocyte remodeling.Figure 1. Intramuscular injectable saNppa-LNP therapy for durable cardioprotection. (ZHANG, Kaiyue, et al., 2026)Mechanistically, single-nucleus transcriptomic analysis (snRNA-seq) revealed that saNppa-LNP treatment reshaped the paracrine profiles of natriuretic peptide receptor-1 positive (Npr1+) endothelial and epicardial cells. This created a pro-regenerative microenvironment that promoted cardiomyocyte cell-cycle reentry and inhibited the expansion of pro-fibrotic periostin-positive (Postn+) fibroblasts. Additionally, longitudinal safety assessments showed only transient local inflammation following treatment, with no evidence of adaptive immune activation or systemic toxicity.In conclusion, this study demonstrates that a single intramuscular injection of saNppa-LNP provides robust and lasting cardioprotection across multiple species and clinically relevant injury models. By leveraging the self-amplifying properties of saRNA and the myocardial-specific activation of Pro-ANP, this minimally invasive, single-dose therapy may offer a safe, simple, and effective strategy for cardiac repair.ReferenceZHANG, Kaiyue, et al. Single intramuscular injection of self-amplifying RNA of Nppa to treat myocardial infarction. Science, 2026, 391.6789: edau9394.
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Engineered T cells, modified to express Chimeric Antigen Receptors (CAR) or T Cell Receptors (TCR), have revolutionized cancer treatment and are currently being explored for the treatment of autoimmune and infectious diseases. Gene editing to enhance T cell function—whether through the disruption of endogenous genes or the precise insertion of DNA payloads—has demonstrated significant potential.However, the current ex vivo manufacturing process is lengthy and expensive, limiting the accessibility of these therapies. Generating CAR-T cells in vivo could overcome these obstacles, but existing methods rely either on transient expression with limited persistence or on random integration of DNA payloads that lack specificity.Recently, a collaborative study by the teams of Justin Eyquem and Jennifer A. Doudna at the University of California, San Francisco, was published online in Nature, titled "In vivo site-specific engineering to reprogram T cells". This research demonstrates that stable and cell-specific transgene expression can be achieved through site-specific integration of large DNA payloads in vivo. The researchers developed a dual-vector system using an enveloped delivery vehicle (EDV) and an adeno-associated virus (AAV) to deliver the CRISPR-Cas9 nuclease complex and the DNA template, respectively. Both vectors were optimized to achieve specific delivery to T cells and high gene-targeting efficiency.By transducing a CAR gene into a T-cell-specific locus, the study successfully generated therapeutic levels of CAR-T cells in vivo within humanized mouse models of B-cell deficiency, as well as in hematologic and solid tumor models. These findings pave the way for more efficient, precise, and accessible T-cell therapies.CAR-T cells represent a promising approach for treating hematologic malignancies; to date, the U.S. Food and Drug Administration (FDA) has approved seven CAR-T cell therapies. Standard CAR-T therapy requires personalized production for each patient, which is limited by inconsistent product quality, long production cycles, and high costs.Typically, CARs are delivered via retroviral vectors, leading to variability in expression results due to random integration. By using CRISPR-Cas9 and adeno-associated virus (AAV)-mediated homology-directed repair (HDR), the CAR can be targeted for integration into the native human TCRα gene locus (TRAC).TRAC-CAR T cells exhibit dynamic CAR expression, which can delay cell exhaustion and improve tumor control in xenograft and immunocompetent models. This work is crucial for the development of allogeneic CAR-T cell therapies, as it disrupts the TCR upon transgene insertion—a necessary step to limit Graft-versus-Host Disease (GvHD).Clinical trials using allogeneic TRAC-CAR T cells derived from healthy donors or induced pluripotent stem cells (iPSCs), combined with intensive lymphodepletion conditioning, have achieved complete remission in patients with hematologic malignancies. Allogeneic therapies can address manufacturing limitations by creating "off-the-shelf" drugs from healthy donors. However, allogeneic CAR-T cells are eventually rejected by the body, and frequent relapses have been observed.Generating CAR-T cells directly in vivo may bypass the various hurdles encountered during leukapheresis and the manufacturing process. It also has the potential to promote the formation of a less-differentiated CAR-T cell population, a trait associated with enhanced anti-tumor activity.To date, efforts to generate CAR-T cells in vivo have utilized randomly integrating viral vectors for sustained CAR expression or lipid nanoparticles (LNPs) for transient expression. Both methods were recently validated in non-human primates and evaluated in a Phase I clinical trial. These approaches face several challenges, including how to efficiently deliver genes to therapeutic doses while avoiding the risk of off-target transduction.Figure 1. Co-delivery of Cas9-EDV and HDRT-AAV generates TRAC-CAR T cells in vitro and in vivo. (NYBERG, William A., et al., 2026)Both delivery and CAR expression should be T-cell specific, as off-target modification of hematopoietic stem cells (HSCs) could lead to mutagenic transformation. Furthermore, CAR expression in tumor cells could prevent the surface expression of target proteins, leading to antigen-negative relapse. LNP delivery of CAR mRNA results in transient expression, which prevents insertional mutagenesis or stable expression in tumor cells, but the required dosage remains unclear.While the envelopes of lentiviral vectors can be engineered to improve T-cell specificity, any non-T cell that is transduced would also express the CAR—posing a potential risk of insertional mutation unless a cell-lineage-specific promoter is used. The researchers hypothesized that integrating a promoterless CAR transgene into the TRAC locus in vivo would enable T-cell-specific and physiological CAR expression while avoiding the ex vivo manufacturing process. Until now, the precise in vivo integration of large DNA payloads in human T cells had not been achieved.Cat.No.Product NamePriceLVG00031ZscFv(EGFR)-CD3zeta?CAR-T?LentivirusInquiryLVG00055ZscFv(MSLN)-CD3zeta?CAR-T?LentivirusInquiryLVG00025ZscFv(CEA)-CD3zeta?CAR-T?LentivirusInquiryLVG00037ZscFv(EPCAM)-CD3zeta?CAR-T?LentivirusInquiryLVG00061ZscFv(PSMA)-CD3zeta?CAR-T?LentivirusInquiryLVG00073ZscFv(Control)-CD3zeta?CAR-T?LentivirusInquiryLVG00001ZscFv(CD19)-CD3zeta?CAR-T?LentivirusInquiryLVG00007ZscFv(CD20)-CD3zeta?CAR-T?LentivirusInquiryLVG00067ZscFv(TACSTD2)-CD3zeta?CAR-T?LentivirusInquiryLVG00013ZscFv(CD33)-CD3zeta?CAR-T?LentivirusInquiryLVG00019ZscFv(CD38)-CD3zeta?CAR-T?LentivirusInquiryLVG00043ZscFv(GPC3)-CD3zeta?CAR-T?LentivirusInquiryLVG00049ZscFv(HER2)-CD3zeta?CAR-T?LentivirusInquiryLVG00074ZscFv(Control)-41BB-CD3zeta?CAR-T?LentivirusInquiryLVG00039ZscFv(EPCAM)-CD28-CD3zeta?CAR-T?LentivirusInquiryThis study developed a method combining AAV with an enveloped delivery vehicle (EDV) for site-specific transgene integration in primary human T cells in vivo. By optimizing the AAV and EDV tools to improve cell-specific delivery efficiency and enhance resistance to human neutralizing antibodies, the researchers were able to generate therapeutic levels of TRAC-CAR T cells in vivo and control tumor growth in multiple humanized mouse models.ReferenceNYBERG, William A., et al. In vivo site-specific engineering to reprogram T cells. Nature, 2026, 1-10.
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Circular RNAs (circRNAs) are primarily generated through the back-splicing of precursor mRNAs, yet their functional targets and underlying mechanisms have remained largely elusive. Recently, researchers from the Institute of Biophysics of the Chinese Academy of Sciences published a research paper titled "Global mapping of circRNA-target RNA interactions reveal P-body-mediated translational repression" online in the journal Molecular Cell. This study introduces circTargetMap—a computational framework for the genome-wide mapping of circRNA targets using RNA-RNA interactomes obtained via RNA in situ conformation sequencing (RIC-seq) across the hippocampus and ten human cell lines. This approach identified 117,163 high-confidence circRNA-target RNA interactions, revealing that 83% of target mRNAs are bound by multiple circRNAs.Functional investigations demonstrated that CDR1as and circRMST sequester target mRNAs into membraneless granules—specifically processing bodies (P-bodies)—through sequence-specific base pairing, thereby inhibiting the translation of these target mRNAs. This process appears to be independent of AGO2, DICER, and microRNAs (miRNAs). To directly capture these granule-associated interactions, the authors developed a method called Granule RIC-seq (GRIC-seq), which revealed a widespread role for circRNA-target RNA interactions in translational repression. Furthermore, pathogenic variants were found to be significantly enriched near circRNA-target RNA interaction sites, suggesting a potential role for these interactions in disease. This research provides a valuable resource for exploring circRNA functions and establishes an analytical framework for studying RNA-RNA interactions within membraneless organelles.CircRNAs are a class of covalently closed RNA molecules formed by the back-splicing of precursor mRNAs. This process connects a downstream splice donor to an upstream splice acceptor site, creating a characteristic back-splice junction (BSJ). This mechanism can generate thousands of distinct circRNAs from various genes. Among them, a subset of circRNAs with high circular-to-linear expression ratios—such as CDR1as (also known as ciRS-7), circRMST, and circHIPK3—exhibit extreme stability and high abundance, and are consistently detected across different cell types and tissues, suggesting evolutionarily conserved regulatory roles. The expression of circRNAs also displays cell-type-specific, tissue-specific, and developmental stage-specific patterns, with particularly high abundance observed in the brain.Cat.No.Product NamePricePMCR-0001EGFP circRNAInquiryPMCR-0002Firefly Luciferase circRNAInquiryPMCR-0003Gaussia Luciferase circRNAInquiryPMCR-0004Renilla Luciferase circRNAInquiryPMCR-0005mCherry circRNAInquiryPMCR-0006β-galactosidase circRNAInquiryPMCR-0007Luciferase P2A GFP circRNAInquiryPMCR-0008Cas9 circRNAInquiryPMCR-0009NLS-Cre circRNAInquiryPMCR-0010Cas9 Nickase circRNAInquiryPMCR-0011Cas9-T2A-EGFP circRNAInquiryPMCR-0012Cre-T2A-EGFP circRNAInquiryPMCR-0013OVA circRNAInquiryPMCR-0014EPO circRNAInquiryPMCR-0015Spike DELTA circRNAInquiryPMCR-0016Spike OMICRON circRNAInquiryPMCR-0017Spike SARS COV-2 circRNAInquiryPMCR-0018HER2/ErbB2 circRNAInquiryAlthough circRNAs have been proven to participate in critical biological processes such as differentiation, cancer, and immune regulation, their target landscapes and mechanisms of action remain unclear. Existing models propose several potential functions for circRNAs, including acting as "molecular sponges" for miRNAs and sequestering RNA-binding proteins (RBPs). The most classic example, CDR1as, contains over 70 conserved binding sites for miR-7, thereby regulating miR-7 availability. Additionally, circRNAs appear to be involved in the regulation of transcription and splicing. However, these functions are primarily derived from isolated case studies, and it remains uncertain whether a broader, generalizable mechanism exists.Given their single-stranded structure and stability, circRNAs may also function through direct base pairing with target RNAs. Recent studies have explored this possibility using 4′-aminomethyl-4,5',8-trimethylpsoralen (AMT)-mediated psoralen crosslinking to capture circRNA-mRNA duplexes, followed by oligonucleotide pull-down and high-throughput RNA sequencing. These methods identified hundreds of circRNAs interacting with mRNAs and several circZNF609-target RNA pairs, but they are limited by low resolution, a lack of precise binding site information, and a reliance on labor-intensive pairwise validation. While bioinformatics predictions for circRNA-mRNA binding sites have been attempted, there is still a lack of a scalable, high-resolution method for the systematic mapping of circRNA-target interactions.Figure 1. Mechanistic Diagram of circTargetMap. (LI, Peng, et al., 2026)This study presents circTargetMap, a computational framework that globally maps circRNA-target RNA interactions by analyzing RIC-seq data—a technology capable of resolving native RNA-RNA interactomes mediated by various RBPs. By applying this framework to data from ten cell lines and human/mouse hippocampi, the authors identified 117,163 high-confidence interactions. They discovered that CDR1as and circRMST inhibit the translation of their targets through direct base pairing—a process independent of Argonaute 2 (AGO2), DICER, or miRNAs—by sequestering targets into membraneless granules such as P-bodies. To map these interactions within granules, the authors developed GRIC-seq, enabling the transcriptome-wide detection of circRNA-mRNA interactions within P-bodies. This revealed a widespread, P-body-mediated mechanism of circRNA-dependent translational repression. Moreover, the significant enrichment of pathogenic variants around circRNA-target RNA junction regions suggests that the disruption of these RNA-RNA interactions may be linked to disease.ReferenceLI, Peng, et al. Global mapping of circRNA-target RNA interactions reveal P-body-mediated translational repression. Molecular Cell, 2026, 86.5: 868-884. e13.
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Chimeric Antigen Receptor (CAR)-Natural Killer (NK) cell therapy holds great promise for treating solid tumors. Still, its application remains limited due to poor infiltration, persistence, and resistance of CAR-NK cells within the tumor microenvironment (TME).Recently, Sidi Chen and Lei Peng from Yale University published a research paper in Nature titled "OR7A10 GPCR engineering boosts CAR-NK therapy against solid tumours". To identify synergistic targets capable of enhancing CAR-NK cell efficacy, the study conducted an unbiased in vivo CRISPR activation (CRISPRa) screen, followed by a barcoded targeted in vivo open reading frame (ORF) screen in primary human CAR-NK cells. The study identified and comprehensively validated OR7A10, a G protein-coupled receptor (GPCR), as the optimal candidate.Figure 1. In in vivo CRISPRa and barcoded ORF screening experiments, OR7A10 was identified as a key factor in enhancing the anti-tumor efficacy of CAR-NK cells. (YANG, Luojia, et al., 2026)By engineering CAR-NK cells to encode OR7A10 cDNA—a method that bypasses CRISPR technology and utilizes a simple manufacturing strategy—the researchers enhanced their proliferation, activation, degranulation, cytokine production, death ligand expression, chemokine receptor expression, cytotoxicity, persistence, metabolic fitness, and resistance to the tumor microenvironment.Cat.No.Product NamePriceAD11576ZHuman OR7A10 adenoviral particlesInquiryLV20634Lhuman OR7A10 (NM_001005190) lentivirus particlesInquiryCDFH013441Human OR7A10 cDNA Clone(NM_001005190.1)InquiryMiUTR1H-07350OR7A10 miRNA 3'UTR cloneInquiryFurthermore, exhaustion was mitigated in primary human NK cells derived from multiple peripheral blood and umbilical cord blood donors. OR7A10-enhanced CAR-NK cells demonstrated robust in vivo efficacy across various solid tumor models. For instance, in an orthotopic breast cancer mouse model, a 100% complete response was achieved, along with long-term tumor control and survival benefits. These findings suggest that OR7A10-engineered CAR-NK cells can serve as a highly effective and mass-producible off-the-shelf therapy for solid tumors.NK cells are cytotoxic lymphocytes with powerful capabilities for anti-tumor activity and the clearance of virus-infected cells. They can bypass Major Histocompatibility Complex (MHC) restrictions and prior immune stimulation. By recognizing gene-encoded ligands associated with oncogenic transformation, NK cells can target cancer cells with low mutational burdens or those lacking neoantigen presentation.Adoptive CAR-NK cell therapy is relatively safe, carries almost no risk of Graft-Versus-Host Disease (GVHD) or Cytokine Release Syndrome (CRS), and is suitable for large-scale industrial production. These advantages have driven research into developing NK-cell-based therapies for solid tumors. As of 2025, over 1,200 clinical trials are evaluating NK cells, including more than 160 trials for CAR-NK cell therapies (ClinicalTrials.gov). In fact, trials have already demonstrated favorable results in treating hematological malignancies.While CAR-NK cell therapy has immense potential for solid tumors, key challenges remain, including limited tumor infiltration, insufficient proliferation, and poor persistence within the tumor microenvironment (TME). Currently, various strategies are being investigated to overcome these limitations, including cytokine engineering and the knockout of inhibitory regulators such as CISH, NKG2A, HIF1A, CALHM2, or CREM33.Although gene knockouts can enhance NK cell function, this approach relies on CRISPR-mediated gene editing, which increases the complexity of cell therapy manufacturing. An alternative strategy involves incorporating "enhancers"—genes with the function of driving overexpression—into the CAR construct, providing a simple and scalable solution for CAR-NK cell manufacturing.This study performed in vivo CRISPRa screening on primary human CAR-NK cells, followed by a targeted small-scale screening of in vivo labeled ORFs, to identify genes that enhance anti-tumor activity in vivo upon overexpression (referred to as "super-enhancers" or "enhancers"). Through these experiments, the study identified a highly potent gene, OR7A10, which boosts CAR-NK cell function and demonstrates powerful anti-tumor effects in vivo.ReferenceYANG, Luojia, et al. OR7A10 GPCR engineering boosts CAR-NK therapy against solid tumours. Nature, 2026, 1-12.
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Integrating artificial intelligence (AI) with advanced robotics to create self-driving labs (SDLs) is a promising approach to solving challenges in molecular discovery. A new SDL system named LUMI-lab combines large-scale molecular pre-training, active learning, and robotics to discover that brominated lipids—previously unrelated to mRNA delivery—can enhance the efficiency of mRNA entry into human cells. This study, led by researchers at the University of Toronto’s Leslie Dan Faculty of Pharmacy, was published in the journal Cell.Supported by an AC Translational Research Grant from the University of Toronto’s Acceleration Consortium, LUMI-lab integrates a molecular foundation model with an automated robotic system. To the research team’s surprise, it identified a new class of mRNA-enhancing lipids—brominated lipid tails—as primary enhancers for increasing transfection efficiency.“Through ten active learning cycles, LUMI-lab synthesized and tested over 1,700 novel lipid nanoparticles (LNPs), discovering brominated ionizable lipids that deliver mRNA into human lung cells with higher efficiency than approved benchmarks,” said Bowen Li, the GSK Chair in Pharmaceutics and Drug Delivery at the University of Toronto’s Leslie Dan Faculty of Pharmacy and an affiliate scientist at the Princess Margaret Cancer Centre, University Health Network. “The key advancement of this AI-driven system is that it independently identified bromination as a significant and meaningful feature without a prior hypothesis and without researchers telling it to look for it first.”Cat.No.Product NamePricePMmRNL-0001EGFP mRNA-LNPInquiryPMmRNL-0002mCherry mRNA-LNPInquiryPMmRNL-0003Firefly Luciferase mRNA-LNPInquiryPMmRNL-0004Cas9-HA mRNA-LNPInquiryPMmRNL-0005EGFP mRNA (no modificaiton)-LNPInquiryPMmRNL-0006mCherry mRNA (no modificaiton)-LNPInquiryPMmRNL-0007Firefly Luciferase mRNA (no modificaiton)-LNPInquiryPMmRNL-0008spCas9 mRNA (no modificaiton)-LNPInquiryPMmRNL-0009spCas9 mRNA (N1-Me-Pseudo UTP modified)-LNPInquiryPMmRNL-0010SARS COV-2 Spike Protein (Alpha Variant) mRNA-LNPInquiryWhile mRNA therapies are one of the fastest-growing drug modalities, they currently rely on lipid nanoparticles for safe delivery to target areas in the human body. To date, only three LNPs have received FDA approval. Platforms like LUMI-lab are expanding the design space by accelerating the discovery of next-generation LNPs needed to unlock new therapeutic applications.Furthermore, SDL models for drug discovery typically rely on large, high-quality datasets to perform well. In emerging fields like mRNA therapy development and delivery, the scarcity of historical data remains a major obstacle. To address this data shortage, the team opted for a foundation-based model, pre-training LUMI-lab on over 28 million molecular structures to allow it to learn general chemical patterns and structures before undertaking more specific tasks.Figure 1. LUMI-lab is a powerful, data-efficient platform for autonomous discovery and optimization of molecules. (Xu, Y., et al., 2026)“When integrated into an active learning framework, the model can be continuously optimized in a closed-loop workflow, further improving its predictive accuracy,” said Li, who also serves as the Canada Research Chair in RNA Vaccines and Therapeutics.When tested in preclinical models, several newly discovered lipids outperformed the lipids used in Moderna’s COVID-19 mRNA vaccine. Although brominated lipids accounted for only 8% of the compound library used by LUMI-lab, they represented more than half of the top-performing candidates. Brominated lipids also demonstrated a safety profile similar to clinical benchmarks, supporting their potential for future therapeutic development.“Next, we are expanding LUMI-lab to simultaneously optimize multiple clinically relevant attributes—not just delivery potency, but also safety, tolerability, and tissue selectivity,” Li said. “Through closed-loop AI predictions and automated experimentation, our goal is to shorten the design cycles for novel lipid materials and open up a larger, evidence-driven chemical space for mRNA therapies.”ReferenceXu, Y., et al. LUMI-lab: A foundation model-driven autonomous platform enabling discovery of ionizable lipid designs for mRNA delivery. Cell, 2026.
Researchers at UT Southwestern Medical Center have discovered that increasing the levels of a protein called BACH2 can make engineered anti-cancer immune cells behave more like stem cells, thereby boosting their therapeutic effectiveness. This study, published in Nature Immunology, proposes a new strategy for improving the efficacy of these immune cells, known as Chimeric Antigen Receptor (CAR) T cells."Using mouse models of solid cancer, we found that programming CAR-T cells to acquire stem-cell-like properties during the manufacturing process significantly enhances their anti-tumor activity. This fine-tuning of CAR-T cells may represent a powerful strategy to overcome key barriers in solid tumor immunotherapy," said Dr. Tuoqi Wu, who co-led the study with Dr. Chen Yao. How CAR-T Cells Work and Their ChallengesSince 2017, CAR-T cells have been approved by the U.S. Food and Drug Administration as a cancer therapy. These cells are created by collecting a patient's own T cells and then genetically engineering them to fight that patient's specific cancer.While CAR-T cells have shown great promise against blood cancers such as leukemia and lymphoma, they only provide durable remission in a portion of cases. Furthermore, CAR-T cells have remained largely ineffective against solid tumors.This inefficiency stems primarily from a phenomenon called exhaustion, Dr. Wu explained. Constant stimulation by antigens on the surface of cancer cells eventually leaves CAR-T cells unable to fight cancer, proliferate, or respond to immune checkpoint inhibitor drugs. They also exhibit signs of metabolic dysfunction and eventually die. Understanding why exhaustion occurs is key to making CAR-T cells a more effective therapy for all cancers.The Link Between Stem-Cell-Like Properties and the BACH2 ProteinA few years ago, Dr. Wu and Dr. Yao found an important clue while studying T-cell exhaustion in chronic viral infections. In that research, T cells showed varying tendencies to exhaust. However, the T cells least prone to exhaustion possessed more stem-cell-like properties. Those cells with higher "stemness" produced more of a protein called BACH2.Figure 1. LT stem-like CAR T cells develop after leukemia clearance and upregulate BACH2 expression. (Hu T, et al., 2026)To test whether this was also true for CAR-T cells, the researchers cultivated these cells from mice. Much like the previous study, cells with higher BACH2 gene expression maintained more stem-cell-like properties than those with lower expression.Cells with more BACH2 were also less prone to exhaustion and more resistant to leukemia than cells with less BACH2. The researchers found similar results when observing BACH2 expression in human CAR-T cell samples.Boosting BACH2 to Improve CAR-T TherapyBased on these findings, the researchers generated mouse CAR-T cells that produced varying levels of BACH2. The CAR-T cells with the highest BACH2 levels maintained the most stem-cell-like properties and were most resistant to exhaustion when grown in lab cultures.Cat.No.Product NamePriceCSC-DC001294Panoply? Human BACH2 Knockdown Stable Cell LineInquiryCSC-SC001294Panoply? Human BACH2 Over-expressing Stable Cell LineInquiryAD01684ZHuman BACH2 adenoviral particlesInquiryLV06017Lhuman BACH2 (NM_001170794) lentivirus particlesInquiryCDCB187124Rabbit BACH2 ORF clone (XM_008263219.1)InquiryCDCR032966Mouse Bach2 ORF clone (NM_001109661.1)InquiryCDFH001615Human BACH2 cDNA Clone(NM_001170794.1)InquiryCDFR003892Rat RGD1311072 cDNA Clone(NM_001033890.1)InquiryCDFR009796Rat RGD1562865 cDNA Clone(NM_001135754.1)InquiryIn another strategy, the researchers transiently increased the amount of BACH2 produced by CAR-T cells during the manufacturing process before injecting them into a mouse model of neuroblastoma—a solid malignancy that develops in nerve precursor cells. Compared to typical CAR-T cells, this adjustment significantly improved the cells' ability to control cancer and inhibited tumor growth.Dr. Wu and Dr. Yao stated that their study suggests increasing BACH2 production in CAR-T cells may provide a viable technology to help them resist exhaustion while fighting both blood tumors and solid tumors. They hope to eventually test this strategy in clinical trials.ReferenceHu T, et al. BACH2 dosage establishes the hierarchy of stemness and fine-tunes antitumor immunity in CAR T cells. Nature Immunology, 2026: 1-11.
The delivery of therapeutic genes is fundamental to gene therapy. Adeno-associated virus (AAV) has become the predominant vehicle for carrying gene payloads due to its superior flexibility in gene splitting and robust gene reconstruction efficiency. However, its limited packaging capacity remains a significant hurdle for the transduction of larger genes.Recently, researchers developed AAV with translocation linking (AAVLINK), a technology that utilizes Cre/lox-mediated intermolecular DNA recombination to achieve the in vivo reassembly of large genes. The related research findings were published in the journal Cell.Figure 1. AAVLINK drove expression of intact Shank3 or SCN1A and rescued behavior and seizure phenotypes of mutant mice, respectively. (Lin J, et al., 2026)Compared to conventional methods, AAVLINK allows for flexible gene-splitting designs, enables highly efficient full-length gene reconstruction, and significantly minimizes the production of aberrant truncated proteins.Utilizing animal models, researchers found that AAVLINK facilitates the robust expression of the full-length Shank3 gene and significantly rescues autism-like behavioral phenotypes in Shank3-deficient mice. Similarly, AAVLINK-mediated delivery of SCN1A, a large gene associated with epilepsy, restored gene expression and alleviated seizure phenotypes in mutant mice. These findings provide strong evidence that AAVLINK supports the functional delivery of large therapeutic genes within the nervous system.Furthermore, the researchers developed AAVLINK 2.0 by integrating a destabilized Cre recombinase. This design offers stricter temporal control over recombination activity, maintaining high gene reconstruction efficiency while reducing potential safety concerns.Cat.No.Product NamePriceAAV00020ZCre Adeno-associated virus(AAV Serotype 5)InquiryAAV00044ZCre Adeno-associated virus(AAV Serotype 1)InquiryAAV00045ZCre Adeno-associated virus(AAV Serotype 2)InquiryAAV00046ZCre Adeno-associated virus(AAV Serotype 6)InquiryAAV00047ZCre Adeno-associated virus(AAV Serotype 8)InquiryAAV00048ZCre Adeno-associated virus(AAV Serotype 9)InquiryAAV00061ZCre-GFP Adeno-associated virus(AAV Serotype 1)InquiryAAV00062ZCre-GFP Adeno-associated virus(AAV Serotype 2)InquiryAAV00063ZCre-GFP Adeno-associated virus(AAV Serotype 5)InquiryAAV00064ZCre-GFP Adeno-associated virus(AAV Serotype 6)InquiryAAV00065ZCre-GFP Adeno-associated virus(AAV Serotype 8)InquiryAAV00066ZCre-GFP Adeno-associated virus(AAV Serotype 9)InquiryAAV00100ZSynapsin-Cre-GFP AAV (Serotype 8)InquiryAAV00111ZAAV9-CMV-Cas9InquiryAAV00123ZscAAV1-CreInquiryUsing the AAVLINK strategy, the researchers constructed a vector library covering 193 large genes associated with genetic disorders, including autism and epilepsy, and validated the gene reconstruction capability of all constructs. The library also includes five CRISPR-based genetic tools, demonstrating the broad applicability of the AAVLINK platform.This study introduces a strategy capable of delivering large gene payloads via AAV, thereby offering therapeutic possibilities for diseases previously considered inaccessible to AAV-based gene therapy.ReferenceLin J, et al. AAVLINK: A potent DNA-recombination method for large cargo delivery in gene therapy. Cell, 2026.
Monoclonal antibodies (mAbs) are a class of critical biomolecules highly valued in diagnostics, research, and therapeutics. Extensive efforts are dedicated to improving the safety and efficacy of antibody therapies through an in-depth understanding of disease mechanisms, precision target screening, and the development of innovative antibody-related products for clinical use.Regulatory standards for the quality of antibody-related products depend heavily on a comprehensive mastery of their structural complexity, functional characteristics, production processes, and control measures. Critical Quality Attributes (CQAs) of mAbs include intrinsic (product-related) properties and extrinsic (process-related) factors.The primary reason for the efficacy of therapeutic monoclonal antibodies lies in their selectivity and the technological advancements driving their development. However, because a single molecule contains multiple functional domains, mAbs are complex proteins both structurally and functionally. This complexity impacts their regulation, production, and quality control. Regulatory scrutiny should carefully consider whether a mAb is fit for its intended use, while taking into account the antibody’s affinity for specific targets, its half-life, and its mechanism of action.Selection and Use of mAb Production Cell SubstratesTo produce bioactive mAbs with the necessary quality and consistency, stable cell lines must be used. If the cell substrate is genetically engineered, the expression system should be characterized in accordance with relevant ICH and WHO guidelines. Before using cell fusion or transformation techniques to immortalize B cells for mAb production, their safety must be carefully evaluated. When using human B lymphocytes as parental cell lines, careful consideration must be given to the possibility of contamination by defective prions or other pathogenic adventitious agents.Post-Processing of Monoclonal Antibody ProductionFollowing the growth and production phases, the recovery of mAbs from the cell substrate requires a procedure capable of consistently producing antibodies that meet their intended use. The specific details of downstream processes and their controls will vary for each product and manufacturer. Viral safety standards must also be met during downstream processing, which should include appropriate viral clearance purification processes based on the production system.Systematic Product Development to Ensure Quality ConsistencyQuality by Design (QbD) represents a systematic approach to product development. To guarantee consistent product quality, safety, and efficacy, this approach requires a deep understanding of the product, the manufacturing process, and the relevant control measures.Good Manufacturing Practice (GMP)GMP standards are developed to reduce trade barriers for pharmaceuticals, facilitate consistency in licensing approvals, and uphold rigorous quality assurance standards throughout the entire process of drug R&D, production, and regulation. The marketing authorization framework ensures that all medical products are evaluated by authorized agencies to verify compliance with safety, quality, and efficacy standards.Sterile Production Processes for Biological ProductsMonoclonal antibodies and vaccines require sterile production procedures to ensure consistent product quality amidst the inherent variability of biological materials.Manufacturing Processes for Biological ProductsVarious technologies, such as microbial and eukaryotic cell culture, biological tissue extraction, recombinant DNA methods, and hybridoma technology, are utilized to obtain biological products, including monoclonal antibodies.Regulatory Guidelines for Contamination PreventionThe European Union and the WHO have issued directives to mitigate the risk of microbial contamination during the manufacturing process, emphasizing compliance with air classification standards such as ISO 14644-1.Importance of Environmental Monitoring in Sterile ProductionRegular environmental monitoring, bioburden assessment, media fills, and container closure integrity testing are critical for maintaining sterility during the production process and must be regularly repeated and updated.Key Steps in Sterile Production ProcessesEssential stages such as final sterilizing filtration, aseptic filling, and vial capping require controlled environments with precise laminar flow conditions and adherence to specific room grades.Bioburden Testing ProceduresBioburden testing is conducted prior to final sterilization, using techniques such as membrane filtration, the pour plate method, and the spread plate method to estimate the number of aerobic microorganisms.Process Simulation Validation via Media Fill TestsMedia fill tests, which simulate sterile production procedures, are successfully completed three consecutive times to ensure process accuracy.HVAC System ConsiderationsHVAC systems play a pivotal role in preventing contamination and cross-contamination; therefore, they require careful consideration during the initial plant design and continuous monitoring of operating parameters.Importance of Filter Integrity Testing in HVAC SystemsHEPA filters in HVAC systems must undergo regular integrity testing, with the frequency of testing varying according to regulatory recommendations.Microbial Environmental Monitoring for Vaccine DistributionRigorous microbial environmental monitoring is essential to minimize microbial risks during the vaccine distribution process, emphasizing cleanrooms and environmental controls, including airborne particulate monitoring.Partner with Creative Biogene for Reliable Biosafety TestingAt Creative Biogene, we take pride in offering comprehensive, reliable, and compliant biosafety testing services that ensure the safety of your biological products. With our expertise, cutting-edge technology, and deep understanding of global regulatory requirements, you can rest assured that your products meet the highest safety standards.ReferenceNikita, A. Rai, A. Verma, et al., The Basics of Large-Scale Commercial Production of Monoclonal Antibodies. Industrial Microbiology and Biotechnology, 2025.
Recently, researchers from Oregon Health and Science University and Washington University in St. Louis published a research paper titled "Intracranial injection of genetically modified, mosquito non-transmissible Zika virus: Safety in primates and ramifications for brain tumor therapy" in the Cell sub-journal, Cell Reports Medicine.Glioblastoma (GBM) is an aggressive brain tumor with a median survival period of less than 21 months. Immune checkpoint inhibitors, peptide vaccines, and dendritic cell vaccines have not shown significant benefits in clinical trials. Over the past two decades, the standard of care for glioblastoma has remained largely unchanged, including surgery, radiation therapy, chemotherapy, and more recently, anti-mitotic Tumor Treating Fields.Glioblastoma typically recurs within 6 months even after maximum treatment, posing a significant clinical challenge. A highly heterogeneous subpopulation of glioblastoma stem cells (GSCs) is resistant to standard therapies and may be the underlying driver of recurrence. Furthermore, its tumor microenvironment (TME) is strongly immunosuppressive and lacks anti-tumor immune cells. Therefore, new therapeutic strategies are needed to address these challenges.Oncolytic viruses can infect and destroy tumor cells, offering a potential treatment for glioblastoma. A range of viruses, including H-1 parvovirus, reovirus, measles virus, Newcastle disease virus, vaccinia virus, poliovirus, adenovirus, herpes simplex virus, retrovirus, myxoma virus, and vesicular stomatitis virus, have been or are being studied as oncolytic virus therapies for GBM. However, these viruses do not exclusively infect glioblastoma stem cells, and to date, no virus has been successfully developed for widespread clinical application.Zika virus (ZIKV)-based oncolytic therapy is unique in that it specifically targets glioblastoma stem cells, shrinking tumor volume and extending survival in various mouse models of glioma.Although Zika virus causes congenital brain abnormalities in fetuses of infected mothers, it rarely infects the brains of adults. The research team demonstrated that ZIKV does not infect adult brain tissue samples from epilepsy surgeries but specifically infects SOX2+ glioblastoma stem cells from human glioblastoma slices. Additionally, in mice, intratumoral oncolytic Zika virus treatment enhanced the effects of systemic antibody-mediated PD-1 blockade.Glioblastoma is an incurable brain tumor. ZIKV has the ability to specifically kill glioblastoma stem cells, which are responsible for treatment resistance. In mouse models of glioblastoma, Zika virus also triggers an anti-tumor inflammatory response and prolongs survival.To support the clinical development of oncolytic Zika virus therapy and address safety concerns regarding intratumoral treatment, the research team modified the 3'untranslated region (3'UTR) of the Zika virus genome by deleting 10 nucleotides—Δ10 3'-UTR ZIKV. This elimination removes the possibility of the virus countering the innate antiviral immune response, and the modified virus cannot be transmitted by mosquitoes.Figure 1. Viral RNA and infectious virus levels in rhesus macaque brains 14 days after intracranial injection of Δ10 3'-UTR ZIKV. (Hirsch A J, et al., 2025).To further evaluate its safety, the research team injected Δ10 3'-UTR ZIKV into the brains of tumor-free rhesus macaques. Following injection, these primates showed no signs of clinical disease. Histologically, as expected, the Zika virus infection triggered mild inflammation that subsided within two weeks. After 14 days, no infectious virus was detected in the brain or any other organs. These findings support the safety of using Δ10 3'-UTR ZIKV in the brain and, combined with previous data, advance its clinical translation as an oncolytic and immunomodulatory therapy for glioblastoma.Cat.No.Product NamePriceCDCV050801ZIKV ancC ORF CloneInquiryCDCV050802ZIKV C ORF CloneInquiryCDCV050803ZIKV preM ORF CloneInquiryCDCV050804ZIKV pr ORF CloneInquiryCDCV050805ZIKV M ORF CloneInquiryCDCV050806ZIKV E ORF CloneInquiryCDCV050807ZIKV NS1 ORF CloneInquiryCDCV050808ZIKV NS2A ORF CloneInquiryCDCV050809ZIKV NS2B ORF CloneInquiryCDCV050810ZIKV NS3 ORF CloneInquiryCDCV050811ZIKV NS4A ORF CloneInquiryCDCV050812ZIKV 2K ORF CloneInquiryCDCV050813ZIKV NS4B ORF CloneInquiryCDCV050814ZIKV NS5 ORF CloneInquiryReferenceHirsch A J, et al. Intracranial injection of genetically modified, mosquito non-transmissible Zika virus: Safety in primates and ramifications for brain tumor therapy. Cell Reports Medicine, 2025, 6(12).
The site-specific insertion of gene-sized DNA fragments remains an unmet need in the field of genome editing. The IS110 family of serine recombinases was recently demonstrated to mediate programmable DNA recombination in bacteria using dual-specific RNA guides, known as bridge RNAs (bRNAs), which simultaneously recognize target and donor sites.Recently, Martin Jinek's team at the University of Zurich, Switzerland, published a research paper entitled "Programmable genome editing in human cells using RNA-guided bridge recombinases" online in Science. This study discovered programmable genome editing in human cells using RNA-guided bridge recombinases.In this study, researchers demonstrated that the bridge RNA-guided recombinase ISCro4, derived from Citrobacter rodentium, exhibits robust activity in human-derived cells. By engineering the bridge RNA to split into independent target-binding loops (TBL) and donor-binding loops (DBL) and applying precise RNA programming rules, they utilized ISCro4 to install kilobase-scale insertions at safe harbor loci, as well as perform programmable deletions and inversions at disease-related loci. Recombination rates for deletions and inversions in genome-integrated reporter constructs exceeded 10%. Furthermore, programmable genomic insertion of exogenous DNA was achieved with efficiencies surpassing 6%.CRISPR-Cas genome editing has revolutionized the treatment of genetic diseases. However, effective treatment for many multi-allelic genetic disorders requires correction strategies based on the site-specific insertion of large, gene-sized DNA payloads. This remains challenging to achieve using existing first- and second-generation CRISPR genome editors. Emerging technologies aiming to address this need include Prime Medicine-assisted site-specific integrase gene editing (PASSIGE), CRISPR-associated transposons (CASTs), engineered retrotransposons, and fusions of catalytically inactive Cas9 with transposases. However, these methods face several limitations, including large coding sizes that may hinder effective cellular delivery, off-target insertions, and the creation of genomic "scars". In this context, the recently discovered bridge RNA-guided recombinases, originating from the IS110 family of bacterial insertion sequence (IS) transposable elements, represent a promising class of programmable systems for genome engineering applications.IS110 bridge recombinases have been shown to catalyze site-specific recombination between target and donor DNA using bipartite RNA guides (referred to as bridge RNAs or seekRNAs). A bridge RNA contains two internal loops: a target-binding loop (TBL) and a donor-binding loop (DBL). Each loop contains two variable segments that base-pair with the top and bottom strands of the target and donor sites, respectively. Structural and biochemical studies of the IS621 recombinase have revealed that the recombination mechanism involves an initial nicking of the top strands of the target and donor, followed by strand exchange and ligation to create a Holliday junction intermediate, which is finally resolved through bottom-strand cleavage and ligation.Figure 1. Structural analysis of ISCro4 to enhance activity. (Pelea O, et al., 2026)In this work, the researchers show that the bridge recombinase ISCro4 is highly active in human cells and provide structural insights into its enhanced activity. Using either plasmid-based or all-RNA delivery, ISCro4 supports the programmable excision and inversion of several thousand base pairs and facilitates the insertion of donor DNA at genomic sites with efficiencies over 6%. Finally, the researchers evaluated the specificity and off-target activity of ISCro4. These results establish a framework for the development of bridge recombinases as next-generation editing tools that surpass current technological capabilities.Catalog No.Product NameInquiryCCPV-001pLX-U6-sgRNAInquiryCCPV-002pLX-sgRNA-zeoInquiryCCPV-003pGL3-U6-sgRNAInquiryCCPV-004pX459InquiryCCPV-005pCW-Cas9InquiryCCPV-006pHDE-35S-Cas9-mCherryInquiryCCPV-007p415-GaL-Cas9-CYC1tInquiryCCPV-008p426-SNR52p-gRNA.CAN1.Y-SUP4tInquiryCCPV-009pCMV-Flag-Cas9InquiryCCPV-010pCDNA-dCas9-VP64InquiryCCPV-011dCas9-VP64_GFPInquiryCCPV-012pHR-SFFV-dCas9-BFP-KRABInquiryCCPV-013pcDNA3.1-hLbCpf1-NLSInquiryCCPV-014pcDNA3.1-hAsCpf1InquiryReferencePelea O, et al. Programmable genome editing in human cells using RNA-guided bridge recombinases. Science, 2026: eadz1884.
