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PubMed2026

Investigating the Contribution of the Imprinted Gene Asb4 to Parental Care.

Genomic imprinting is a form of epigenetic regulation that leads to expression from one parental allele only and, in animals, is unique to mammals. Imprinted gene expression is predominant in the brain and their roles in neural processes are becoming more appreciated. Recent analyses have indicated an enrichment of imprinted gene expression in the 'parental hub' circuitry. Specifically, imprinted genes were over-represented in the transcriptomic profile of galanin positive (Gal+) neurons in the medial preoptic area (MPOA) of the hypothalamus. One of those imprinted genes showing enriched expression in Gal+ neurons was the maternally expressed Asb4. Here, we propose that Asb4 supports normal activation of MPOA Gal+ neurons required for parental care. We aim to demonstrate abnormal parental behaviours-such as decreased pup retrieval and impaired nest building-and activity of MPOA Gal+ neurons in brain-specific maternal Asb4 knockout mice and hypothesis knockout animals will demonstrate a deficient behavioural phenotype in one or more parental behavioural characteristics.

Animals↗

PubMed2025

Adult bi-paternal offspring generated through direct modification of imprinted genes in mammals.

Imprinting abnormalities pose a significant challenge in applications involving embryonic stem cells, induced pluripotent stem cells, and animal cloning, with no universal correction method owing to their complexity and stochastic nature. In this study, we targeted these defects at their source-embryos from same-sex parents-aiming to establish a stable, maintainable imprinting pattern de novo in mammalian cells. Using bi-paternal mouse embryos, which exhibit severe imprinting defects and are typically non-viable, we introduced frameshift mutations, gene deletions, and regulatory edits at 20 key imprinted loci, ultimately achieving the development of fully adult animals, albeit with a relatively low survival rate. The findings provide strong evidence that imprinting abnormalities are a primary barrier to unisexual reproduction in mammals. Moreover, this approach can significantly improve developmental outcomes for embryonic stem cells and cloned animals, opening promising avenues for advancements in regenerative medicine.

Animals↗

PubMed2026

Mammalian DNA methyltransferases in DNA methylation and imprinted gene expression in extraembryonic ectoderm of post-implantation embryos.

DNA methylation in mammals is mainly catalyzed by three DNA methyltransferases (DNMTs). Conventionally, DNMT1 is considered the primary DNMT protein for maintenance DNA methylation, whereas DNMT3A and DNMT3B function in de novo DNA methylation. In two previous studies, we demonstrated that DNMT3A and DNMT3B maintain genome-wide DNA methylation in embryonic stem (ES) cells and in the epiblast of post-implantation embryos. Interestingly, DNMT3A and DNMT3B also sustain genome-wide DNA methylation in the extraembryonic ectoderm (EXE) of post-implantation embryos, including repeats, genic and intergenic regions. Although DNMT1 plays a major role in maintaining DNA methylation at the imprinting control regions (ICRs) in the imprinted regions, DNMT3A and DNMT3B are required for preserving DNA methylation at the ICRs of a subset of imprinted regions in EXE, similar to the observations in ES cells and epiblast. Surprisingly, de novo DNA methylation mediated by DNMT3A and DNMT3B leads to increased DNA methylation at a large subset of imprinted regions. These results are consistent with what we previously elucidated in the epiblast of post-implantation embryos. Importantly, loss of DNA methylation at the ICR of an imprinted region, resulting from the absence of DNMT1 or two DNMT3 proteins, causes allelic expression switch of the corresponding imprinted genes in that imprinted region. This study provides further evidence that DNMT3A and DNMT3B exert both maintenance and de novo DNA methylation functions across the genome in post-implantation embryos. It also validates some previous findings for DNA methylation-dependent allelic expression switch of imprinted genes.

DNA methylation↗

PubMed2025

MDR1 DNA glycosylase regulates the expression of genomically imprinted genes and Helitrons.

Targeted demethylation by DNA glycosylases (DNGs) results in differential methylation between parental alleles in the endosperm, which drives imprinted expression. Here, we performed RNA sequencing on endosperm derived from DNG mutant mdr1 and wild-type (WT) endosperm. Consistent with the role of DNA methylation in gene silencing, we find 108 genes and 96 TEs differentially expressed (DE) transcripts that lost expression in the hypermethylated mdr1 mutant. Compared with other endosperm transcripts, the mdr1 targets are enriched for TEs (particularly Helitrons), and DE genes are depleted for both core genes and GO term assignments, suggesting that the majority of DE transcripts are TEs and pseudo-genes. By comparing DE genes to imprinting calls from prior studies, we find that the majority of DE genes have maternally biased expression, and approximately half of all maternally expressed genes (MEGs) are DE in this study. In contrast, no paternally expressed genes (PEGs) are DE. DNG-dependent imprinted genes are distinguished by maternal demethylation and expression primarily in the endosperm, so we also performed Enzymatic Methyl-seq on hybrids to identify maternal demethylation and utilized a W22 gene expression atlas to identify genes expressed primarily in the endosperm. Overall, approximately ⅔ of all MEGs show evidence of regulation by DNGs. Taken together, this study solidifies the role of MDR1 in the regulation of maternally expressed, imprinted genes and TEs and identifies subsets of genes with DNG-independent imprinting regulation.

Genomic Imprinting↗

PubMed2025

Rescue of imprinted genes by epigenome editing in human cellular models of Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is a genomic imprinting disorder caused by the loss of function of the paternal chromosome 15q11-13, resulting in a spectrum of symptoms associated with hypothalamic dysfunction. PWS patients lack the expression of paternally expressed genes (PEGs) in the 15q11-13 locus but possess an epigenetically silenced set of these genes in the maternal allele. Thus, activation of these silenced genes can serve as a therapeutic target for PWS. Here, we leverage CRISPR-based epigenome editing system to modulate the DNA methylation status of the PWS imprinting control region (PWS-ICR) in induced pluripotent stem cells (iPSCs) derived from PWS patients. Successful demethylation in the PWS-ICR restores the PEG expression from the maternal allele and reorganizes the methylation patterns in other PWS-associated imprinted regions beyond the PWS-ICR. Remarkably, these corrected epigenomic patterns and PEG expression are maintained following the differentiation of these cells into hypothalamic organoids. Finally, the single-cell transcriptomic analysis of epigenome-edited organoids demonstrates a partial restoration of the transcriptomic dysregulation observed in PWS. This study highlights the utility of epigenome editing technology as a therapeutic approach in addressing PWS and potentially other imprinting disorders.

Prader-Willi Syndrome↗

PubMed2025

Perinatal Lead (Pb) Exposure Increases Mouse Embryonic Weight and Alters Neuronal Gene Expression.

Acute and chronic exposure to lead (Pb) during pregnancy is linked to adverse health outcomes, including delayed neurodevelopment in offspring. However, the pathways by which Pb exposure influences long-term health remain poorly understood. To address this, we measured the effects of perinatal Pb exposure on gene expression including imprinted genes, X-linked genes, and sexually dimorphic genes. Female mice were given control or Pb acetate dosed (32 ppm) drinking water two weeks prior to timed mating until embryonic day (E)10-12, upon which whole embryos were collected, weighed, and sexed at E13-15. From a subset of embryo heads (n≥9 per sex per group), we extracted and sequenced RNA. We used linear regression to assess Pb impacts on embryonic weight and gene expression across all mice and stratified by sex. Among the differentially expressed genes, we identified significantly enriched pathways. Pb-exposed embryos weighed more than controls (p=0.007), across both sexes. Collectively, we identified 2,920 differentially expressed genes (FDR<0.05), including 31 imprinted genes and 120 X-linked genes upon Pb exposure. Pb exposure altered expression in gene pathways related to neuronal structure and function as well as sexually dimorphic genes (44 for females; 76 for males). These findings highlight perinatal Pb-linked alterations that may drive later-life health outcomes.

DOHaD↗

PubMed2026

Combined effects of urine exposure and cryopreservation on sperm quality: an in vitro study of retrograde ejaculation.

Sperm quality influences fertility and offspring health through both genomic inheritance and epigenetic inheritance. Thus, for use in clinical-assisted reproductive technology (ART), spermatozoa must have optimal genomic and epigenetic structures. In patients with retrograde ejaculation, spermatozoa are usually recovered from urine and then cryopreserved for ART. However, the effects of urine exposure and subsequent freeze-thaw cycles on sperm quality remain unclear. This is particularly true for epigenetic changes and their underlying mechanisms. In this study, we examined how different durations of urine exposure (10 min and 40 min) followed by freeze-thaw cycles affected sperm motility, DNA integrity, and methylation levels of imprinting genes (H19-imprinted maternally expressed transcript [ H19 ], mesoderm-specific transcript [ MEST ], and the transposable element Alu [ Alu ]). As the duration of urine exposure increased, sperm motility (median [interquartile range]) decreased from 48.0% (39.0%-52.5%) to 1.0% (1.0%-5.0%), the DNA fragmentation index (DFI; median [interquartile range]) increased from 12.0% (9.3%-19.9%) to 23.5% (13.9%-33.9%), the MEST methylation level (mean ± standard deviation [s.d.]) increased from 3.8% ± 1.5% to 11.5 ± 1.2%, and the H19 methylation level (mean ± s.d.) decreased from 86.9% ± 0.9% to 82.1% ± 0.5%. The freeze-thaw process further reduced sperm motility, while the DFI and methylation levels of MEST and H19 did not significantly change. The Alu methylation level remained stable. These findings demonstrate that urine exposure affects sperm motility, DNA integrity, and methylation levels of some imprinting genes. These effects intensify over time. In contrast, the freeze-thaw process impacts only sperm motility. In clinical practice, minimizing exposure to urine might improve sperm quality.

Humans↗

PubMed2026

Parent-of-origin specific allelic expression in outbreeding Arabidopsis arenosa identifies antagonistic parental enrichment in protein degradation pathways.

In plants, the epigenetic phenomenon of parent-of-origin allele-specific expression occurs mainly in the triploid endosperm. Although well studied in inbreeding Arabidopsis thaliana, genomic imprinting has been less investigated in outcrossers. In order to investigate a wider role of parental-specific allelic expression, we have analyzed imprinting in whole seeds of the obligate outbreeder Arabidopsis arenosa. High-throughput analysis of imprinting in outbreeding species is hampered by the lack of reference genomes and available sequenced accessions. High degree of allelic variation in outbreeding species may also limit the analysis to loci with less variation. We developed a reference-independent pipeline to detect parental-specific reads. Using different accessions in reciprocal crosses, we detected more than 70 paternally biased imprinted genes and > 500 maternally biased genes. Paternally biased genes showed major enrichment for proteins with ubiquitin protein transferase and ligase activity. Maternally biased genes were enriched for protein pathways directly counteracting paternally enriched genes. Here, we demonstrate an alignment-free protocol to identify imprinted genes that may be successfully applied for imprinting studies in other highly heterozygous outcrossing species. Our results suggest a unique role of genomic imprinting affecting post-transcriptional gene regulation in outbreeding A. arenosa.

Arabidopsis arenosa↗

PubMed2024

Epigenetic footprints: Investigating placental DNA methylation in the context of prenatal exposure to phenols and phthalates.

BACKGROUND: Endocrine disrupting compounds (EDCs) such as phthalates and phenols can affect placental functioning and fetal health, potentially via epigenetic modifications. We investigated the associations between pregnancy exposure to synthetic phenols and phthalates estimated from repeated urine sampling and genome wide placental DNA methylation. METHODS: The study is based on 387 women with placental DNA methylation assessed with Infinium MethylationEPIC arrays and with 7 phenols, 13 phthalates, and two non-phthalate plasticizer metabolites measured in pools of urine samples collected twice during pregnancy. We conducted an exploratory analysis on individual CpGs (EWAS) and differentially methylated regions (DMRs) as well as a candidate analysis focusing on 20 previously identified CpGs. Sex-stratified analyses were also performed. RESULTS: In the exploratory analysis, when both sexes were studied together no association was observed in the EWAS. In the sex-stratified analysis, 114 individual CpGs (68 in males, 46 in females) were differentially methylated, encompassing 74 genes (36 for males and 38 for females). We additionally identified 28 DMRs in the entire cohort, 40 for females and 42 for males. Associations were mostly positive (for DMRs: 93% positive associations in the entire cohort, 60% in the sex-stratified analysis), with the exception of several associations for bisphenols and DINCH metabolites that were negative. Biomarkers associated with most DMRs were parabens, DEHP, and DiNP metabolite concentrations. Some DMRs encompassed imprinted genes including APC (associated with parabens and DiNP metabolites), GNAS (bisphenols), ZIM2;PEG3;MIMT1 (parabens, monoethyl phthalate), and SGCE;PEG10 (parabens, DINCH metabolites). Terms related to adiposity, lipid and glucose metabolism, and cardiovascular function were among the enriched phenotypes associated with differentially methylated CpGs. The candidate analysis identified one CpG mapping to imprinted LGALS8 gene, negatively associated with ethylparaben. CONCLUSIONS: By combining improved exposure assessment and extensive placental epigenome coverage, we identified several novel genes associated with the exposure, possibly in a sex-specific manner.

Humans↗

PubMed2025

Modeling early gastrulation in human blastoids with DNA methylation patterns of natural blastocysts.

Blastoids are a promising model for studying early human embryogenesis, but current models have limitations in post-implantation development and lack comprehensive epigenetic assessments, especially regarding genomic imprinting. These issues can lead to failures in accurately modeling early embryonic development. In this study, we developed a high-fidelity blastoid model using 4 chemicals + leukemia inhibitory factor (LIF) (4CL) naive human pluripotent stem cells (hPSCs) (4CL blastoids). 4CL blastoids closely resemble human blastocysts in morphology and transcriptional profiles, exhibiting similar DNA methylation and gene imprinting patterns. By extending the 3D culture to 14 days, these blastoids mimic early gastrulation, demonstrating the specification and migration of cells. They also show the transcriptional signature of hemogenic angioblast (HAB) cells at Carnegie stage 6 (CS6). This model bridges pre- and post-implantation stages, offering valuable insights into early tissue formation and human development.

Humans↗

PubMed2025

Analysis of a BCOR internal tandem duplication in mouse embryonic stem cell to neuronal precursor differentiation.

BCOR (BCL-6 corepressor) is a component of variant Polycomb Repressive Complex 1.1 (vPRC1.1), one of several vPRC1 complexes that catalyze histone H2A ubiquitination thought to play an important role in PRC2 binding and the deposition of H3K27me3 to silence genes. The PCGF Ub-like fold discriminator (PUFD) domain at the C-terminus of BCOR forms a heterodimer with PCGF1, serving as a critical interface for its polycomb-dependent functions. Internal tandem duplication (ITD) mutations in BCOR, causing in-frame duplications of 20 to 40 amino acids in the PUFD domain, are observed in heterogeneous tumors including sarcomas (kidney, bone, and endometrium) and neuroepithelial tumors in the brain. To dissect the molecular mechanisms underlying aberrant function of BCOR-ITD mutants, we employed mouse embryonic stem (mES) cells expressing either transgenic or endogenous BCOR-ITD. Our results indicate that the BCOR-ITD mutation does not disrupt the BCOR-PCGF1 interaction, instead maintaining the integrity of the vPRC1.1 complex. While displaying subtle changes in imprinted gene expression during differentiation toward a neural lineage, BCOR-ITD mutants also had no growth phenotype in culture. Furthermore, we found that CD24+ cells were enriched, as expected, during neural progenitor differentiation in both wildtype and mutant cells. However, sensitization of BCOR-ITD mES cells with EZH2 inhibitor during differentiation resulted in an unexpected enrichment of a CD24+CD26+ subpopulation, indicating aberrant cell fate that was also prevalent in a BCOR truncation mutant. Together, our results suggest that BCOR-ITD may largely retain wildtype function, but with increased susceptibility to synergistic stress on the Polycomb pathway.

Animals↗

PubMed2026

Prader-Willi syndrome as a neurogenetic model for psychosis and obsessive-compulsive disorder: A review of clinical, behavioral, and biological insights.

Prader-Willi syndrome (PWS) is a complex neurodevelopmental disorder classically defined by hyperphagia and obesity. However, its profound psychiatric phenotype offers a unique genetic framework for understanding major mental illnesses. This review positions PWS as a potentially informative biological model for psychosis and obsessive-compulsive disorder (OCD), bridging the gap between 15q11-q13 imprinting defects and neural circuit dysfunction. We synthesize evidence demonstrating that psychosis in PWS is not a uniform trait but is disproportionately linked to the maternal uniparental disomy (mUPD) subtype. This genotype-phenotype correlation suggests that overexpression of maternally imprinted genes and loss of paternal expression disrupt cortical excitatory-inhibitory balance, resembling the "schizophrenia-bipolar" genomic architecture. Furthermore, synthesized evidence characterizes the repetitive, ritualistic behaviors in PWS not merely as behavioral challenges, but as a developmentally arrested OCD-spectrum phenotype driven by distinct serotonergic-oxytocinergic imbalances and hypothalamic-limbic dysconnectivity. Mechanistic insights from preclinical models of MAGEL2, SNORD116, and NDN deficiency are integrated with clinical findings to highlight shared neurobiological substrates. Finally, we outline a roadmap for precision psychiatry in PWS, emphasizing the necessity of pharmacogenomics in antipsychotic management and the potential of targeted circuit-based therapeutics. By deconstructing the psychiatric comorbidities of PWS, we provide a framework for translating genomic architecture into mechanistic understanding and targeted treatment for complex neuropsychiatric disorders.

15q11-q13↗

PubMed2026

Deoxyribonucleic acid methylation abnormalities at imprinted loci in oligospermic and azoospermic men.

OBJECTIVE: To assess deoxyribonucleic acid (DNA) methylation at imprinted and repetitive genomic regions in ejaculated and testicular sperm from men with oligospermia, azoospermia, and those undergoing vasectomy reversal (VR), compared with fertile controls. DESIGN: Observational case-control study. SUBJECTS: Samples were obtained from 68 men, including 29 infertile men (18 oligospermic [5-15 million/mL], 11 severely oligospermic [<5 million/mL]) and 20 fertile controls with confirmed natural conceptions. Testicular tissue was collected from 11 azoospermic men (7 obstructive azoospermia [OA], 4 nonobstructive azoospermia [NOA]) and 8 men with prior paternity undergoing VR. EXPOSURE: Sperm DNA methylation at four imprinted genes (H19, GTL2, MEST, and LIT1) and one repetitive element (LINE1). MAIN OUTCOME MEASURES: Methylation levels at CpG sites determined by bisulfite pyrosequencing. RESULTS: The H19 was significantly hypomethylated only in severe oligospermia compared with fertile controls, whereas other groups showed nonsignificant trends with overlapping distributions. In contrast, MEST was significantly hypermethylated in oligospermic, azoospermic, and VR groups compared with fertile controls. No significant differences were observed for GTL2, LIT1, or LINE1. CONCLUSION: The DNA methylation abnormalities in sperm are locus-specific and vary across infertility phenotypes. MEST alterations were consistent across groups, whereas H19 changes were limited to severe oligospermia. Similar methylation patterns in testicular sperm from azoospermic and VR groups suggest that epigenetic alterations may reflect the testicular environment or obstruction, or differences between testicular and ejaculated sperm.

Humans↗

PubMed2026

Fetal hypoxia causes oocyte oxidative stress damage via the Sirt3/Sod2 pathway and can be alleviated by nicotinamide mononucleotide.

Environmental hypoxia exerts detrimental effects on the reproductive capabilities of both humans and animals. A fetal hypoxia model was established in which fetal mice were kept in a high-plateau hypoxic setting from embryonic day (E) 0 to 16.5. In our previous research, we found that fetal hypoxia exposure perturbs the methylation of imprinted genes in adult sperm and causes intergenerational placental impairments in male offspring. However, the specific impacts of fetal hypoxia on the female reproductive system, particularly regarding oocyte maturation, remain poorly understood. First, we found that fetal hypoxia mice exhibited a significant reduction in the average number of pups per litter. We conducted a comprehensive analysis of the transcriptome in oocytes from the hypoxic group and investigated the metabolic alterations within the follicular microenvironment. Fetal hypoxic stress contributed to cleavage and blastocyst rate reduction and induced early apoptosis and DNA damage triggered by mitochondrial dysfunction, oxidative stress aggravation and Sirt3/Sod2 downregulation. Additionally, administration of nicotinamide mononucleotide (NMN) has been shown to prevent oocytes from mitochondrial dysfunction and developmental impairment by increasing the expression of Sirt3/Sod2 and autophagy. The number of pups per litter in fetal hypoxia mice was reduced by 57.7% compared to the control group, while NMN intervention could restore it to 73.1% of the control group. These results indicate that fetal hypoxia exposure exerts multiple potential damages to adult female reproduction, while highlighting the clinical potential of NMN supplementation as a targeted intervention to alleviate such hypoxia-associated female reproductive impairment.

Animals↗

PubMed2025

Dynamic allelic expression in mouse mammary glands across the adult developmental cycle.

The mammary gland, which primarily develops postnatally, undergoes significant changes during pregnancy and lactation to facilitate milk production. Through the generation and analysis of 480 transcriptomes, we provide the most detailed allelic expression map of the mammary gland, cataloguing cell-type-specific expression from ex-vivo purified cell populations over 10 developmental stages, enabling comparative analysis. The work identifies genes involved in the mammary gland cycle, parental-origin-specific and genetic background-specific expression at cellular and temporal resolution, genes associated with human lactation disorders and breast cancer. Genomic imprinting, a mechanism regulating gene expression based on parental origin, is crucial for controlling gene dosage and stem cell potential throughout development. The analysis identified 25 imprinted genes monoallelically expressed in the mammary gland, with several showing allele-specific expression in distinct cell types. No novel imprinted genes were identified and the absence of biallelically expressed imprinted genes suggests that, unlike in brain, selective absence of imprinting does not regulate gene dosage in the mammary gland. This research highlights transcriptional dynamics within mammary gland cells and identifies novel candidate genes potentially significant in the tissue during pregnancy and lactation. Overall, this comprehensive atlas represents a valuable resource for future studies on expression and transcriptional dynamics in mammary cells.

Animals↗

PubMed2025

Overcoming gene dosage barriers in mammalian development: An imprinting balancing act.

Genomic imprinting ensures parent-of-origin gene expression and prevents uniparental development. In this issue of Cell Stem Cell, Li et al.1 extensively engineered androgenic haploid embryonic stem cells to overcome imprinting barriers, producing adult bi-paternal mice, albeit with low efficiency, and providing insights into roles of imprinted genes in development.

Genomic Imprinting↗

PubMed2026

Allele-specific chromatin architecture shapes imprinted domains and coordinates a distal enhancer and antisense transcription at the mouse Mest-Copg2 domain.

Genomic imprinting results in parent-of-origin-dependent gene expression, but how three-dimensional genome organization contributes to imprinted gene regulation remains unclear. Using Capture Hi-C in mouse cortex and primary cortical neurons, we identified parental allele-specific chromatin architectures across multiple imprinted domains. These architectures largely originate from imprinting control regions and correlate with DNA methylation-sensitive CTCF binding. Active and inactive alleles of imprinted genes show distinct promoter interaction profiles and differential engagement with distal regulatory elements in both contact frequency and the epigenetic state of distal regions. A CRISPR interference screen identified a distal enhancer that regulates Mest-Copg2 imprinted expression through allele-specific chromatin interactions. In neurons, this enhancer activates Copg2 on the maternal allele, whereas on the paternal allele it drives Mest isoforms transcribed antisense to Copg2 and contributes to Copg2 repression. In summary, we show that allele-specific chromatin architecture coordinates maternal enhancer activity and paternal antisense transcription to control imprinted expression in neurons.

Animals↗

PubMed2026

CAR-T Cell Therapy: Manufacturing Platforms and Clinical Consequences.

Chimeric antigen receptor (CAR) T-cell therapy has transformed hematological cancer care, yet variability in efficacy, durability, and safety cannot be explained solely by antigen selection or patient factors. We propose that manufacturing platforms are active biological determinants of outcome. Viral vectors, used in all licensed products, provide stable genomic integration and durable expression but are limited by cost, cargo capacity, and centralized production. Nonviral strategies, including transposons, CRISPR knock-ins, and messenger RNA delivery, enable faster, less-expensive manufacturing with larger payloads, while introducing distinct safety and persistence profiles. This review presents a three-layer mechanistic framework that reframes manufacturing as biology: integration biology determines genomic risk and transgene stability; clonal fitness shapes persistence, dominance, and exhaustion; and epigenomic imprinting, influenced by gene transfer method, cytokines, and culture stress, preconfigures functional trajectories. Clinical observations link platform choice to immune recovery, where prolonged B-cell aplasia and delayed T-cell reconstitution contribute to infection-related nonrelapse mortality, and hematopoietic reserve at apheresis emerges as a practical predictor. Finally, manufacturing is positioned as the key to democratizing cell therapy. Decentralized, nonviral production aligned with regulatory standards may enable equitable access and transition CAR-T therapy from innovation to sustainable global care.

Humans↗