Kathryn J Citrano, Vidhya Bharathi Maheswari Jawahar, Madison M Reeves, Leonardo Petrucelli, Yari Carlomagno, Mei Yue, Jorge Alaiz Noya, Lillian M Daughrity, Raul Baena Tomé, Karen Jansen-West, Bailey Rawlinson, Michael DeTure, Erica Engelberg-Cook, Alpana Singh, Neill R Graff-Radford, Gregory S Day, Bradley F Boeve, Adam L Boxer, David S Knopman, Keith A Josephs, Ronald C Petersen, Björn Oskarsson, Nicholas J Ashton, Dennis W Dickson, Tania F Gendron, Mercedes Prudencio, Yong-Jie Zhang, Leonard Petrucelli
{"title":"Anti-HDGFL2 cryptic protein antibodies provide a sensitive readout of TDP-43 pathology and clinical disease features.","authors":"Kathryn J Citrano, Vidhya Bharathi Maheswari Jawahar, Madison M Reeves, Leonardo Petrucelli, Yari Carlomagno, Mei Yue, Jorge Alaiz Noya, Lillian M Daughrity, Raul Baena Tomé, Karen Jansen-West, Bailey Rawlinson, Michael DeTure, Erica Engelberg-Cook, Alpana Singh, Neill R Graff-Radford, Gregory S Day, Bradley F Boeve, Adam L Boxer, David S Knopman, Keith A Josephs, Ronald C Petersen, Björn Oskarsson, Nicholas J Ashton, Dennis W Dickson, Tania F Gendron, Mercedes Prudencio, Yong-Jie Zhang, Leonard Petrucelli","doi":"10.1016/j.xcrm.2026.103105","DOIUrl":"https://doi.org/10.1016/j.xcrm.2026.103105","url":null,"abstract":"<p><p>TAR DNA-binding protein (TDP-43) cytoplasmic aggregates and nuclear depletion contribute to TDP-43 dysfunction in frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) and forms of motor neuron disease (MND), particularly amyotrophic lateral sclerosis (ALS). TDP-43 regulates alternative splicing, but its dysfunction can engender the inclusion of cryptic exons (CEs) during splicing. Transcripts harboring an in-frame CE can generate de novo proteins. One example is the CE variant of hepatoma-derived growth factor-like protein 2 (HDGFL2-CE). To understand HDGFL2-CE as a readout of TDP-43 dysfunction, and its spatial relationship with TDP-43 pathology, we generate anti-HDGFL2-CE polyclonal and monoclonal antibodies and develop sensitive HDGFL2-CE immunoassays. With these tools, we observe that HDGFL2-CE accumulates in neurons with TDP-43 pathology, and that higher frontal cortex HDGFL2-CE in FTLD-TDP and FTLD-TDP/MND associates with greater pathological TDP-43, earlier age of onset, and shorter survival, supporting HDGFL2-CE as a marker tightly linked to TDP-43 dysfunction and clinical disease features.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103105"},"PeriodicalIF":14.0,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149147421","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
John H Klich, Anahita Nejatfard, Emily L Meany, Ben S Ou, Zuzanna D Krawczyk, Julie Baillet, Eric A Appel
{"title":"Spatially tuned localization of interleukins and OX40 agonists enhances synergistic anti-tumor immunity.","authors":"John H Klich, Anahita Nejatfard, Emily L Meany, Ben S Ou, Zuzanna D Krawczyk, Julie Baillet, Eric A Appel","doi":"10.1016/j.xcrm.2026.103109","DOIUrl":"10.1016/j.xcrm.2026.103109","url":null,"abstract":"<p><p>While advances in immunotherapy have revolutionized care for cancer patients, most approaches still fail to mount a robust anti-cancer effect. To address this challenge, the field has turned to combination immunotherapies, but systemic administration of potent combination therapies has resulted in severe immune-related adverse effects. Here, we use an injectable polymer-nanoparticle (PNP) hydrogel to rationally localize immunotherapeutic cytokines (IL-12 and IL-2) intratumorally and antibodies (OX40a) peritumorally. We hypothesize that selectively altering the biodistribution of these cargo enables tolerable and synergistic anti-cancer combinations. Using in vivo imaging, we demonstrate that administration sites are critical for redistributing cargo to either the tumor or tumor-draining lymph node (tdLN). Further, we demonstrate that this approach synergistically improved treatment efficacy in the B16F10 and MC38 tumor models and alters cellular phenotypes, resulting in significant tumor clearance in both single and double tumor models.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103109"},"PeriodicalIF":14.0,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149148494","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Christopher Forcados, Hakan Köksal, Eveline Scherer, Rafaela Abrantes, Pierre Dillard, Henrique O Duarte, Sarah Josefsson, Catarina Gomes, Constance de Montlaur, Henrik T Z Hellesøy, Ryan Dunkel, Erlend B Smeland, June H Myklebust, Celso A Reis, Emmet McCormack, Pascal Gelebart, Else Marit Inderberg, Sébastien Wälchli
{"title":"Reviving low-affinity glycan-targeting CAR with combinatorial design.","authors":"Christopher Forcados, Hakan Köksal, Eveline Scherer, Rafaela Abrantes, Pierre Dillard, Henrique O Duarte, Sarah Josefsson, Catarina Gomes, Constance de Montlaur, Henrik T Z Hellesøy, Ryan Dunkel, Erlend B Smeland, June H Myklebust, Celso A Reis, Emmet McCormack, Pascal Gelebart, Else Marit Inderberg, Sébastien Wälchli","doi":"10.1016/j.xcrm.2026.103108","DOIUrl":"https://doi.org/10.1016/j.xcrm.2026.103108","url":null,"abstract":"<p><p>CD19CAR T cells demonstrate remarkable therapeutic efficacy in the treatment of B cell malignancies. A global limitation of conventional CD19CAR therapy is its mono-specificity. Thus, defining complementary targets to CD19 is critical to avoid target-dependent limitations. Alternatives to protein antigens include secondary modifications, such as glycosylation. One example of aberrant glycosylation in lymphoma is the increase in N-glycans capped with α2,6-linked sialic acid, named CD75s. Here, we generate a CAR that recognizes CD75s based on an IgM monoclonal antibody called HH2. HH2CAR shows cytotoxic activity against B cell lymphoma cell lines, although it induces little to no cytokine release. However, while HH2CAR alone cannot control tumor progression in vivo, its combination with CD19CAR results in a functional molecule. Beyond overcoming the limited efficiency of HH2CAR T cells, this combination also prevents potential off-tumor/on-target toxicity associated with CD19 single targeting. Thus, inefficient mono-specific CAR molecules can be effectively leveraged in combinatorial formats.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103108"},"PeriodicalIF":14.0,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149135162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"A spatiotemporal atlas of radiation-induced brain injury reveals dysfunction of the blood-CSF barrier.","authors":"Cheng Quan, Yan Gao, Xinyi Liu, Jiabao Xiang, Jiashu Zhang, Liping Chen, Ying Li, Weiming Gao, Kaina Hao, Guohang He, Di Liu, Aogang Wang, Hongyue Tian, Hao Lu, Jie Ping, Siao Jiang, Qilin Huang, Yinglong Wu, Haitao Wu, Yiming Lu, Gangqiao Zhou","doi":"10.1016/j.xcrm.2026.103097","DOIUrl":"https://doi.org/10.1016/j.xcrm.2026.103097","url":null,"abstract":"<p><p>Radiotherapy for brain tumors frequently induces irreversible cognitive decline, yet the underlying mechanisms remain poorly understood. Here, we present an integrated single-cell and spatial transcriptomic atlas of radiation-induced brain injury (RIBI) in mice, spanning the acute to chronic phases. We reveal that the early-delayed phase following irradiation represents a critical window during which the blood-cerebrospinal fluid barrier (BCSFB) integrity is compromised. This disruption results from the selective depletion of a radiosensitive Tmsb4x<sup>+</sup> epithelial subpopulation in the choroid plexus, which functions as a gatekeeper for the BCSFB. Consequently, CSF-derived macrophages excessively infiltrate the periventricular niche and engage in spatial crosstalk with interferon-responsive microglia. This dysregulated immune axis sustains chronic neuroinflammation, driving the late-stage neurodegeneration and cognitive impairment. In conclusion, our study establishes a high-resolution spatiotemporal framework and positions the BCSFB as a pivotal immune gateway and a promising therapeutic target for mitigating RIBI.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103097"},"PeriodicalIF":14.0,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149135046","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Prognostic value of cfDNA methylation in locally advanced esophageal squamous cell cancer treated with neoadjuvant immunochemoradiotherapy.","authors":"Baoqing Chen, Zimeng Li, Yin Li, Xingyuan Cheng, Wendi Xuzhang, Ruixi Wang, Yilu Gao, Peiying Cen, Chen Yi, Lirong Tian, Guangkuo Wei, Zhengyang Li, Bingzhong Jing, Shuchun Wang, Qiaoqiao Li, Hong Yang, Huiyan Luo, Mian Xi","doi":"10.1016/j.xcrm.2026.103102","DOIUrl":"https://doi.org/10.1016/j.xcrm.2026.103102","url":null,"abstract":"<p><p>We prospectively evaluated whether longitudinal cfDNA methylation predicts pathological complete response (pCR) and survival in 70 patients with esophageal squamous cell carcinoma (ESCC) receiving neoadjuvant immunochemoradiotherapy. Serial plasma samples (n = 183) were collected at four time points: pre-neoadjuvant treatment (NAT), post-NAT, pre-surgery, and post-surgery. Targeted whole-genome cfDNA methylation sequencing was performed, and cancer detection (CD) values were calculated with positivity, defined as CD ≥ 0.7. CD positivity dropped from 74% pre-NAT to 31% post-NAT (p < 0.001). Pre-surgery CD positivity was significantly higher in non-pCR versus pCR patients (33% vs. 0%; p = 0.028). A model incorporating post-NAT CD value and clinical factors achieved an area under the curve (AUC) of 0.764 for pCR. Post-NAT CD-negative patients had significantly improved disease-free survival (DFS; hazard ratio [HR] = 0.33; p = 0.035). Findings were reproduced in an expanded 30-patient cohort. Dynamic cfDNA methylation monitoring is associated with pCR and DFS, warranting further validation in larger cohorts.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103102"},"PeriodicalIF":14.0,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149135151","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Microbiota-mediated naringenin release limits postoperative acute gastrointestinal injury by suppressing ferroptosis.","authors":"Fan Deng, Jingjuan Hu, Yue Min, Sun Xie, Zebin Lin, Qishun Sun, Huamin Liu, Shiying He, Siyuan Feng, Ling Wu, Xiaofeng Chen, Linghong Xu, Zheang Zhang, Wenqi Tang, Zhuang Li, Hongwei Zhou, Kexuan Liu","doi":"10.1016/j.xcrm.2026.103101","DOIUrl":"https://doi.org/10.1016/j.xcrm.2026.103101","url":null,"abstract":"<p><p>Acute gastrointestinal injury (AGI) remains a major complication after cardiopulmonary bypass, yet its microbiome-related determinants are unclear. We identify microbiota-mediated naringenin (NAR) release as a candidate modulator of AGI susceptibility. Patients who subsequently develop AGI have lower preoperative fecal NAR levels and β-glucuronidase (GUS) activity, accompanied by reduced abundance of Bacteroides vulgatus (B. vulgatus). In germ-free and conventional mice, B. vulgatus alleviates intestinal ischemia-reperfusion injury through GUS-dependent release of NAR from its glucuronide conjugate. Mechanistically, NAR engages the TLR4/MyD88-SPRR2A axis to suppress CHAC1-driven ferroptosis, thereby maintaining epithelial integrity and promoting mucosal repair in vivo and in organoids. Clinically, preoperative fecal NAR concentration and GUS activity show exploratory value as noninvasive markers for postoperative AGI risk stratification. Collectively, these findings support a microbiota-host metabolic model in which microbial NAR release may mitigate postoperative gastrointestinal injury by restricting ferroptosis, with potential implications for risk assessment and therapeutic modulation.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103101"},"PeriodicalIF":14.0,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149135089","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lei Zhao, Shan An, Mengqian Gao, Cui Shen, Meng Li, Yangjing Li, Ning Liu, Jin Chen, Wenjun Wan, Lichen Yin, Yiran Zheng
{"title":"Lipid-engineered antibody-based therapeutics target inflamed joints and lymph nodes to enhance rheumatoid arthritis treatment.","authors":"Lei Zhao, Shan An, Mengqian Gao, Cui Shen, Meng Li, Yangjing Li, Ning Liu, Jin Chen, Wenjun Wan, Lichen Yin, Yiran Zheng","doi":"10.1016/j.xcrm.2026.103094","DOIUrl":"https://doi.org/10.1016/j.xcrm.2026.103094","url":null,"abstract":"<p><p>Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation and joint damage. Although antibody (Ab)-based biologic disease-modifying anti-rheumatic drugs (bDMARDs) have transformed RA treatment, their efficacy remains limited in many patients. Here, we conjugate Ab-based bDMARDs with pegylated diacyllipid (DP) motifs to enable their albumin hitchhiking after subcutaneous administration, thereby targeting these lipid-drug conjugates (LDCs) to both inflamed joints and lymph nodes (LNs) for enhanced and concurrent immunosuppression. Multivalent DP conjugation allows bDMARDs larger than albumin to engage multiple albumin molecules, further enhancing albumin-mediated targeting. In a collagen-induced arthritis model, DP modification substantially improves the therapeutic efficacy of two representative bDMARDs, TNF-α-neutralizing Ab (aTNF-α) and CTLA4-immunoglobin recombinant protein (CTLA4), without detectable additional safety risks. bDMARDs bearing two DP moieties significantly outperform their single-DP-modified counterparts, consistent with more extensive albumin engagement. LDC offers a potent, facile, and broadly applicable strategy for targeting Ab-based therapeutics to inflamed tissues and LNs.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103094"},"PeriodicalIF":14.0,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149135122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jérôme Delplanque, Audrey Leloire, Lauriane Le Collen, Hélène Loiselle, Bénédicte Toussaint, Emmanuel Vaillant, Frédéric Allegaert, Timothée Beke, Guillaume Charpentier, Sylvia Franc, Beverley Balkau, Michel Marre, Emma Henriques, Emmanuel Buse Falay, Mehdi Derhourhi, Philippe Froguel, Amélie Bonnefond
{"title":"Human genetic evidence challenges NCOA1 as a monogenic obesity gene.","authors":"Jérôme Delplanque, Audrey Leloire, Lauriane Le Collen, Hélène Loiselle, Bénédicte Toussaint, Emmanuel Vaillant, Frédéric Allegaert, Timothée Beke, Guillaume Charpentier, Sylvia Franc, Beverley Balkau, Michel Marre, Emma Henriques, Emmanuel Buse Falay, Mehdi Derhourhi, Philippe Froguel, Amélie Bonnefond","doi":"10.1016/j.xcrm.2026.103106","DOIUrl":"https://doi.org/10.1016/j.xcrm.2026.103106","url":null,"abstract":"<p><p>Obesity is a heterogeneous disease with a substantial genetic component. Rare pathogenic variants in genes of the leptin-melanocortin pathway can cause monogenic obesity and support targeted therapies such as setmelanotide, a melanocortin 4 receptor agonist. Pathogenic variants in NCOA1, encoding the nuclear receptor co-activator SRC-1, have recently been proposed as a cause of monogenic obesity through impaired leptin-induced POMC activation, leading to the inclusion of NCOA1 variant carriers in the EMANATE setmelanotide trial. However, despite biological rationale, the contribution of NCOA1 variants to human obesity remains elusive. Here, we assess NCOA1 variants with case-control analyses in adults and children from the RaDiO study, combined with in vitro assays and replication in the UK Biobank. We find no association between pathogenic NCOA1 variants and obesity or body mass index.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103106"},"PeriodicalIF":14.0,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149134985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Regional brain aging signatures predict mortality through neurovascular immune mechanisms.","authors":"Pei-Lin Lee, Yi-Long Huang, Chih-Kuang Liang, Wei-Ju Lee, Li-Ning Peng, Fei-Yuan Hsiao, Ching-Po Lin, Liang-Kung Chen","doi":"10.1016/j.xcrm.2026.103096","DOIUrl":"https://doi.org/10.1016/j.xcrm.2026.103096","url":null,"abstract":"<p><p>Brain aging provides an integrative marker of systemic health, but whether regional patterns outperform whole-brain approaches remains unknown. Here, we show that regional brain age signatures achieve superior mortality prediction through identifiable neurovascular-immune mechanisms in 1,240 community-dwelling adults followed for 10 years (120 deaths). While global brain age independently predicts mortality (hazard ratio [HR], 1.044 per year), a data-driven three-region model combining the left precentral gyrus, left parahippocampal gyrus, and right cerebellum achieves superior discrimination (C-index, 0.81 vs. 0.79, p = 0.032). Integration with plasma proteomics (513 proteins) reveals complement activation and adaptive immune dysregulation as convergent mechanisms. Region-specific vulnerabilities emerge: microvascular dysfunction in the motor cortex, proteostasis failure in the medial temporal structures, and iron dysregulation in the cerebellum. Longitudinal imaging (n = 444) identifies accelerated brain aging phenotypes predicting cognitive decline (HR, 1.558; p = 0.042). These findings establish regional neuroimaging-proteomic integration as a precision strategy linking network-specific vulnerabilities to systemic immune processes.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103096"},"PeriodicalIF":14.0,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149126810","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chenxi Yang, Shuxin Guo, Yaming Lu, Minrun Duan, Hao Yang, Weishen He, Yujie Cheng, Fujian Wan, Yuxuan Han, Shengfeng Wan, Huifang Ma, Junbin Wang, Cong Tang, Jun Wen, Kun Xu, Sheng Liu, Bo Shu, Shuijun Zhang, Niu Huang, Shuaiyao Lu, George F Gao, Lianpan Dai
{"title":"Fusion-loop-engineered Zika mRNA vaccine elicits convergent B cell immunodominance to uncouple protection from ADE in macaques.","authors":"Chenxi Yang, Shuxin Guo, Yaming Lu, Minrun Duan, Hao Yang, Weishen He, Yujie Cheng, Fujian Wan, Yuxuan Han, Shengfeng Wan, Huifang Ma, Junbin Wang, Cong Tang, Jun Wen, Kun Xu, Sheng Liu, Bo Shu, Shuijun Zhang, Niu Huang, Shuaiyao Lu, George F Gao, Lianpan Dai","doi":"10.1016/j.xcrm.2026.103091","DOIUrl":"https://doi.org/10.1016/j.xcrm.2026.103091","url":null,"abstract":"<p><p>Antibody-dependent enhancement (ADE) remains a major hurdle for flavivirus vaccine development. Engineering the fusion loop (FL) represents a promising solution, yet validations restricted to murine models limit human translatability due to profound species divergence. Here, we provide a primate-level demonstration that FL-engineered Zika virus (ZIKV)-M/E mRNA vaccination protects against ZIKV challenge with negligible dengue virus (DENV) ADE. The vaccine-induced B cells are overwhelmingly ZIKV specific (>97%), dominated by a convergent population using a germline ortholog of human IGHV5-10-1, a gene preferentially recruited during natural human ZIKV infection. Antibodies derived from this population are highly potent and, mechanistically, achieve multi-stage viral entry blockade. Cryo-electron microscopy analysis reveals that these antibodies target a distinct, vulnerable hotspot on ZIKV. Notably, ZIKV specificity is dictated by the epitope residues D67-M68-A69, whereas a homologous DENV N67-linked glycan imposes steric shielding to preclude cross-reactivity. Our findings demonstrate that FL engineering uncouples protective immunity from ADE for safer human flavivirus vaccines.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103091"},"PeriodicalIF":14.0,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149126768","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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