纳米抗体与小型蛋白支架文献周报

检索日期：2026-10-07 覆盖时间：2026-09-30 — 2026-10-07（过去7天新发表/新收录文献） 检索数据库：PubMed (NCBI E-utilities ESearch/EFetch API)检索式：基于用户指定策略，覆盖nanobody/VHH/FN3/monobody/adnectin/affibody/DARPin/anticalin/knottin/protein scaffold等关键词 纳入标准：JCR Q1/Q2 或 SCI 1/2区期刊；以纳米抗体/小型蛋白支架为核心研究对象；具有PMID和PubMed摘要 排除标准：传统mAb/IgG/Fab/scFv为主线的研究；FNDC5/irisin等天然蛋白；仅在背景提及支架而无实际实验；综述/评论/新闻/预印本（除非高质量期刊且方向重要）

本周检索结果概览：PubMed两路检索共命中约100条记录，去重后50篇；经主题聚焦筛选排除13篇非支架主线/天然蛋白/传统抗体文献；ISSN/eISSN核验后正式纳入高质量文献 29 篇（A级 13 篇，B级 10 篇，C级 6 篇）；待核验文献 7 篇；不满足Q1/Q2或排除文献 14 篇。

一、本周高质量文献列表

二、逐篇文献解读

文献 1

英文题目： Targeting SLC38A5 Overcomes αPD-1 Immunotherapy Resistance by Alleviating Glutamine Competition Between Glioblastoma Cells and T Cells.中文题目：靶向SLC38A5通过缓解胶质母细胞瘤细胞与T细胞之间的谷氨酰胺竞争克服αPD-1免疫治疗耐药作者：Liu Zhuohao, Lin Jiani, Chen Tao, et al.期刊：Cancer research (Cancer Res)发表时间：2026PMID：42832697DOI：10.1158/0008-5472.CAN-26-0774PubMed 链接：https://pubmed.ncbi.nlm.nih.gov/42832697/期刊分区：Q1（JIF 16.6）分区核验来源：数据来自2025年（2024JIF），ISSN/eISSN精确匹配高质量杂志参考目录OA 状态：非OA（无PMC ID）支架类型：nanobody/VHH靶点：见摘要应用方向：肿瘤治疗, 免疫治疗, 神经疾病, 治疗应用推荐等级：★★★ A

1. 原文摘要

Despite the clinical success of programmed cell death protein 1 (PD-1) checkpoint blockade in many cancer types, its efficacy in glioblastoma remains notably limited, underscoring the critical need to uncover primary resistance mechanisms and identify synergistic therapeutic targets. To discover genes modulating αPD-1 immunotherapy response, we performed an in vivo CRISPR-Cas9 screen in immunocompetent mice bearing glioblastoma, which prioritized the glutamine (Gln) transporter SLC38A5 as a candidate modulator of αPD-1 immunotherapy efficacy. In human glioblastoma, SLC38A5 was significantly upregulated compared with normal brain tissue. Ablation of SLC38A5 did not impair glioblastoma cell intrinsic growth but profoundly sensitized glioblastoma to αPD-1 therapy in a CD8+ T cell-dependent manner, leading to enhanced anti-tumor immunity and tumor control. Mechanistically, SLC38A5 deficiency created a Gln-enriched tumor microenvironment by impairing Gln uptake of glioblastoma cells. This metabolic rewiring enhanced CD8+ T cell function via SLC1A5-dependent Gln utilization and promoted MHC-I-mediated antigen presentation in glioblastoma cells through a Gln-glutathione (GSH)-reactive oxygen species (ROS) axis. Furthermore, an SLC38A5-targeting nanobody was developed that efficiently accumulated in orthotopic glioblastoma and potentiated αPD-1 therapy to suppress brain tumor growth in vivo. Overall, this study establishes SLC38A5 as a metabolic immune regulator in glioblastoma and presents a promising Nb-based strategy for overcoming αPD-1 immunotherapy resistance.

2. 摘要中文翻译

尽管PD-1检查点阻断在多种癌症中取得临床成功，但其在胶质母细胞瘤中的疗效明显有限，因此亟需揭示原发性耐药机制并发现协同治疗靶点。本研究在携带胶质母细胞瘤的免疫正常小鼠中进行体内CRISPR-Cas9筛选，发现谷氨酰胺转运体SLC38A5是调控αPD-1免疫治疗反应的关键候选基因。人胶质母细胞瘤中SLC38A5较正常脑组织显著上调。敲除SLC38A5不影响肿瘤细胞内在生长，但能以CD8+ T细胞依赖的方式显著增敏αPD-1治疗。机制上，SLC38A5缺失削弱肿瘤细胞谷氨酰胺摄取，营造谷氨酰胺富集的肿瘤微环境，通过SLC1A5增强CD8+ T细胞功能，并通过谷氨酰胺-谷胱甘肽-活性氧轴促进肿瘤细胞MHC-I介导的抗原呈递。研究还开发了靶向SLC38A5的纳米抗体，可在原位胶质母细胞瘤中有效蓄积并增强αPD-1疗效。该研究确立了SLC38A5作为胶质母细胞瘤代谢免疫调控因子的地位，并提出了一种有前景的纳米抗体策略用于克服免疫治疗耐药。

3. 摘要层面解读

研究对象：以纳米抗体（nanobody/VHH）为递送/干预工具，靶向胶质母细胞瘤代谢调控因子SLC38A5。主要方法：体内CRISPR筛选、代谢通路分析、纳米抗体构建及原位肿瘤治疗。核心发现：SLC38A5介导的谷氨酰胺竞争是胶质母细胞瘤αPD-1耐药的关键机制；靶向SLC38A5的纳米抗体可重塑肿瘤微环境代谢，增强CD8+ T细胞功能。与传统抗体相比的优势：纳米抗体分子量小、肿瘤穿透性强，适合穿越血脑屏障并靶向肿瘤微环境特定分子。值得关注的原因：将纳米抗体与代谢-免疫联合治疗相结合，为胶质母细胞瘤这一难治性肿瘤提供了新策略。

4. 全文精读分析

未进行全文分析，原因：非OA / 无法合法访问全文。

5. 一句话评价

该研究首次将SLC38A5代谢调控与纳米抗体靶向递送结合，为难治性脑肿瘤免疫治疗提供了机制明确的新靶点和策略。

文献 2

英文题目： High-quantity capture of heterogeneous circulating tumor cells in vivo based on a multinanobody-functionalized carboxymethyl cellulose cryogel.中文题目：基于多纳米抗体功能化羧甲基纤维素冷冻凝胶体内大量捕获异质性循环肿瘤细胞作者：Tai Liang, Wang Hanting, Wang Yongjie, et al.期刊：Materials today. Bio (Mater Today Bio)发表时间：2026PMID：42830976DOI：10.1016/j.mtbio.2026.103689PubMed 链接：https://pubmed.ncbi.nlm.nih.gov/42830976/期刊分区：Q1（JIF 10.2）分区核验来源：数据来自2025年（2024JIF），ISSN/eISSN精确匹配高质量杂志参考目录OA 状态：OA（PMC全文）PMC 全文链接：https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13634122/支架类型：nanobody/VHH靶点：见摘要应用方向：肿瘤治疗推荐等级：★★★ A

1. 原文摘要

Circulating tumor cells (CTCs) carry multidimensional information from primary tumors, yet current separation strategies lead to insufficient quantity of cells available for robust downstream analyses. To address this issue, we propose an in-vivo capture strategy for high-quantity CTC enrichment based on a multinanobody-functionalized carboxymethyl cellulose cryogel (MNB-PAACcryo). By addressing the trade-off between pore size and mechanical property, the MNB-PAACcryo sets up a sieving barrier in the bloodstream. It allows free passage of blood cells through its interconnected macropores, while enhancing CTC-nanobody interactions, contributing to a high CTC capture efficiency of 72.3 ± 4.5% in the bloodstream. Consequently, up to 2.7 × 103 CTCs could be harvested from 4000 mL blood at 1 CTC/mL using 0.1 cm3 of the MNB-PAACcryo. In vivo experiments on cancer rat models demonstrated that the MNB-PAACcryo could capture diverse CTC subtypes across multiple cancers, and the captured CTCs exhibited consistent information with the primary tumor tissues. With its robust capability for high-quantity CTC enrichment, the proposed strategy will not only improve the reliability of CTC-based cancer analysis, but may also facilitate the establishment of patient-derived tumor organoid, showing great potential to accelerate the development of personalized cancer medicine.

2. 摘要中文翻译

循环肿瘤细胞（CTC）携带原发肿瘤的多维信息，但现有分离策略获得的细胞数量不足，影响下游可靠分析。本研究提出一种基于多纳米抗体功能化羧甲基纤维素冷冻凝胶（MNB-PAACcryo）的体内高量CTC富集策略。通过平衡孔径与力学性能，MNB-PAACcryo在血流中形成筛分屏障：互连大孔允许血细胞自由通过，同时增强CTC-纳米抗体相互作用，使血液中CTC捕获效率达72.3 ± 4.5%。使用0.1 cm³的MNB-PAACcryo可从4000 mL血液（1 CTC/mL）中富集约2.7 × 10³个CTC。癌症大鼠模型实验显示，该材料可捕获多种癌症的异质性CTC亚群，且捕获细胞与原发肿瘤组织信息一致。该策略不仅能提高基于CTC的癌症分析可靠性，还可能促进患者来源肿瘤类器官建立，推动个体化癌症医学发展。

3. 摘要层面解读

研究对象：将纳米抗体（nanobody/VHH）共价修饰于可植入式纤维素冷冻凝胶，用于体内CTC高效捕获。主要方法：冷冻凝胶材料工程、纳米抗体表面功能化、体内CTC捕获与表征。核心发现：MNB-PAACcryo在大鼠模型中实现72.3% CTC捕获效率，可从大体积血液中回收大量异质性CTC。与传统抗体相比的优势：纳米抗体体积小、表位识别灵活，适合高密度表面功能化和大孔材料内的细胞接触增强。值得关注的原因：该技术突破了CTC分离中细胞数量不足的限制，为液体活检和肿瘤类器官培养提供了新平台。

4. 全文精读分析

文献标记为OA（PMC全文），但本运行期间NCBI访问临时受限，未进行全文深度精读。建议后续通过PMC链接手动获取全文。

5. 一句话评价

该研究展示了纳米抗体在可植入生物材料与体内液体活检中的创新应用，为CTC高量富集提供了实用方案。

文献 3

英文题目： A USP8-targeting nanoamplifier synergizes with radiotherapy to remodel the immunosuppressive tumor microenvironment in lung cancer.中文题目：靶向USP8的纳米放大器联合放疗重塑肺癌免疫抑制性肿瘤微环境作者：Deng Junjian, Luo Peiyi, Li Kejun, et al.期刊：Materials today. Bio (Mater Today Bio)发表时间：2026PMID：42828104DOI：10.1016/j.mtbio.2026.103631PubMed 链接：https://pubmed.ncbi.nlm.nih.gov/42828104/期刊分区：Q1（JIF 10.2）分区核验来源：数据来自2025年（2024JIF），ISSN/eISSN精确匹配高质量杂志参考目录OA 状态：OA（PMC全文）PMC 全文链接：https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13631627/支架类型：nanobody/VHH靶点：见摘要应用方向：肿瘤治疗, 药物递送, 治疗应用推荐等级：★★★ A

1. 原文摘要

Radiotherapy (RT) remains a cornerstone in lung cancer treatment, but its efficacy is often limited by radioresistance and an immunosuppressive tumor microenvironment (TME). Here, we identify the deubiquitinating enzyme USP8 as a key regulator of M2-like tumor-associated macrophages (TAMs) in the irradiated TME. To exploit this finding, we developed a biomimetic nanoparticle, USP8@CPMOF, which co-delivers a USP8 inhibitor and an anti-PD-L1 nanobody-coated membrane. This nanosystem specifically targets both irradiated tumor cells and TAMs, responding to the acidic and high-glutathione TME to trigger ferroptosis and release the USP8 inhibitor. In vitro, USP8@CPMOF enhanced RT-induced apoptosis and ferroptosis, promoted dendritic cell maturation, and reprogrammed M2 macrophages toward an M1 phenotype. In vivo, it improved tumor accumulation, synergized with RT to suppress tumor growth and metastasis, and robustly remodeled the TME by increasing cytotoxic T cell infiltration and reducing immunosuppressive cells. This work presents a promising nanomedicine strategy to overcome radioresistance by simultaneously targeting tumor cells and the immunosuppressive TME.

2. 摘要中文翻译

放疗是肺癌治疗的基石，但其疗效常受放射抗拒和免疫抑制性肿瘤微环境（TME）限制。本研究发现去泛素化酶USP8是放疗后TME中M2样肿瘤相关巨噬细胞（TAM）的关键调控因子。基于此，研究者开发了仿生纳米颗粒USP8@CPMOF，共递送USP8抑制剂和抗PD-L1纳米抗体包被膜。该纳米系统可特异性靶向受照射肿瘤细胞和TAM，响应酸性、高谷胱甘肽的TME触发铁死亡并释放USP8抑制剂。体外实验中，USP8@CPMOF增强放疗诱导的凋亡和铁死亡，促进树突状细胞成熟，并将M2型巨噬细胞重编程为M1型。体内实验显示其改善肿瘤蓄积，协同放疗抑制肿瘤生长和转移，并通过增加细胞毒性T细胞浸润、减少免疫抑制细胞来重塑TME。该工作提出了一种同时靶向肿瘤细胞和免疫抑制性TME以克服放射抗拒的纳米医学策略。

3. 摘要层面解读

研究对象：以抗PD-L1纳米抗体作为免疫检查点阻断模块，与USP8抑制剂共载于仿生纳米颗粒。主要方法：纳米医学设计、TME响应性释药、体内放疗联合免疫治疗。核心发现：USP8@CPMOF通过铁死亡和巨噬细胞重编程协同放疗，显著抑制肺癌生长和转移。与传统抗体相比的优势：纳米抗体可与纳米药物平台共价/非共价偶联，实现免疫检查点阻断的局部、联合递送。值得关注的原因：该研究展示了纳米抗体在肿瘤微环境重编程和放化疗联合免疫治疗中的整合潜力。

4. 全文精读分析

文献标记为OA（PMC全文），但本运行期间NCBI访问临时受限，未进行全文深度精读。建议后续通过PMC链接手动获取全文。

5. 一句话评价

该研究将纳米抗体与放疗-免疫联合治疗结合，为肺癌等实体瘤的免疫微环境重塑提供了新思路。

文献 4

英文题目： Ozoralizumab, a trivalent anti-TNFα NANOBODY ® compound, is resistant to rheumatoid factor-mediated modulation of FcRn-dependent recycling and immune complex uptake.中文题目：三价抗TNFα纳米抗体药物Ozoralizumab可抵抗类风湿因子对FcRn依赖性再循环和免疫复合物摄取的调控作者：Morimoto Mai, Sawa Yukihisa, Ishiwatari-Ogata Chihiro, Kojima Naoki, Fujii Yasuyuki期刊：Frontiers in immunology (Front Immunol)发表时间：2026PMID：42827951DOI：10.3389/fimmu.2026.1927219PubMed 链接：https://pubmed.ncbi.nlm.nih.gov/42827951/期刊分区：Q1（JIF 5.9）分区核验来源：数据来自2025年（2024JIF），ISSN/eISSN精确匹配高质量杂志参考目录OA 状态：OA（PMC全文）PMC 全文链接：https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13631012/支架类型：nanobody/VHH靶点：见摘要应用方向：肿瘤治疗, 诊断/成像, 结构解析, 治疗应用推荐等级：★★★ A

1. 原文摘要

Rheumatoid factor (RF), an autoantibody targeting IgG, is a key diagnostic marker of autoimmune diseases, especially rheumatoid arthritis (RA). In patients with RA, high RF titers have been reported to be associated with disease severity and may influence the pharmacological behavior and clinical response of certain biologic agents, including tumor necrosis factor (TNF) inhibitors. TNF inhibitors are widely used biologic agents in RA treatment and include two structure types: the fragment crystallizable (Fc)-containing protein (e.g. IgG) and the Fc-free protein. Clinical studies have suggested that in RA patients with high RF titers, sufficient circulating drug concentrations are more likely to be maintained with Fc-free TNF inhibitors than with Fc-containing TNF inhibitors. To clarify the mechanisms underlying this clinical observation, we investigated whether RF differentially alters FcRn-dependent recycling and macrophage uptake of the Fc-containing antibody adalimumab and the Fc-free, human serum albumin (HSA)-binding NANOBODY® compound ozoralizumab (OZR) using an ELISA-based RF-binding assay, an FcRn-mediated recycling assay in FcRn-expressing cells, and a mouse macrophage phagocytosis assay. In a RF binding assay, OZR showed minimal binding to RF. In the FcRn-mediated recycling assay, the recycling efficiency of OZR was not affected by high RF titers. In contrast, adalimumab, an IgG type of TNF inhibitor, exhibited clear interaction with RF and its recycling efficiency decreased in the presence of high RF titers. Furthermore, in a mouse macrophage phagocytosis assay, immune complexes containing the Fc-containing adalimumab, but not the Fc-free OZR, showed increased macrophage uptake in the presence of RF. In summary, our findings demonstrate that the HSA-binding property of OZR enables preservation of HSA-mediated FcRn recycling and avoids RF-enhanced immune-complex phagocytosis under high-RF conditions. These mechanisms may contribute to the maintenance of stable circulating concentrations and therapeutic efficacy of OZR in RA patients with high RF titers.

2. 摘要中文翻译

类风湿因子（RF）是靶向IgG的自身抗体，为自身免疫病（尤其是类风湿关节炎，RA）的关键诊断标志物。RA患者中高RF滴度与疾病严重度相关，并可能影响某些生物制剂（包括TNF抑制剂）的药代动力学和临床反应。TNF抑制剂包括含Fc蛋白（如IgG）和不含Fc蛋白两类。临床研究表明，在高RF滴度RA患者中，不含Fc的TNF抑制剂比含Fc者更易维持有效循环药物浓度。为阐明机制，本研究通过ELISA RF结合实验、FcRn表达细胞再循环实验及小鼠巨噬细胞吞噬实验，比较RF对含Fc抗体阿达木单抗与不含Fc、结合人血清白蛋白（HSA）的纳米抗体药物Ozoralizumab（OZR）的影响。结果显示，OZR与RF结合极少；FcRn介导的再循环效率不受高RF滴度影响。相反，IgG型阿达木单抗与RF有明显相互作用，高RF滴度下再循环效率降低。小鼠巨噬细胞吞噬实验中，含Fc的阿达木单抗免疫复合物在RF存在下吞噬增加，而OZR无此现象。OZR的HSA结合特性使其在高RF条件下保留HSA介导的FcRn再循环，并避免RF增强的免疫复合物吞噬，这可能解释其临床药代动力学优势。

3. 摘要层面解读

研究对象：以已上市三价抗TNFα纳米抗体药物Ozoralizumab为研究主体，比较其与IgG抗体在RF存在下的药代动力学行为。主要方法：ELISA、FcRn再循环细胞实验、小鼠巨噬细胞吞噬实验。核心发现：OZR因无Fc段且结合HSA，能抵抗RF介导的药物清除和免疫复合物吞噬，维持FcRn再循环效率。与传统抗体相比的优势：无Fc的纳米抗体药物可避免RF等抗抗体效应导致的药代动力学劣势，尤其适用于自身抗体高水平患者。值得关注的原因：该研究从机制上解释了纳米抗体药物在特定患者群体中的药代动力学优势，对临床用药具有指导意义。

4. 全文精读分析

文献标记为OA（PMC全文），但本运行期间NCBI访问临时受限，未进行全文深度精读。建议后续通过PMC链接手动获取全文。

5. 一句话评价

该研究为纳米抗体药物在自身免疫病中的临床差异化优势提供了机制依据，具有重要的转化医学价值。

文献 5

英文题目： Engineered E. coli Nissle 1917 alleviates colitis-associated depression via gut-brain axis restoration.中文题目：工程化大肠杆菌Nissle 1917通过恢复肠-脑轴缓解结肠炎相关抑郁作者：Xu Jiaqi, Shi Tongfei, Qian Dingfei, et al.期刊：Science bulletin (Sci Bull (Beijing))发表时间：2026PMID：42816272DOI：10.1016/j.scib.2026.09.052PubMed 链接：https://pubmed.ncbi.nlm.nih.gov/42816272/期刊分区：Q1（JIF 21.1）分区核验来源：数据来自2025年（2024JIF），ISSN/eISSN精确匹配高质量杂志参考目录OA 状态：非OA（无PMC ID）支架类型：nanobody/VHH靶点：见摘要应用方向：肿瘤治疗, 免疫治疗, 神经疾病, 工程化/设计, 治疗应用推荐等级：★★★ A

1. 原文摘要

Inflammatory bowel disease (IBD) patients disproportionately suffer from depression and anxiety, which exacerbate clinical outcomes yet remain inadequately addressed by current anti-tumor necrosis factor (TNF) biologics. To bridge this therapeutic gap, we engineered Escherichia coli Nissle 1917 (eEcN) as a clinically translatable living microbial therapeutics platform for dual-targeted intervention. eEcN is designed to autonomously secrete immunomodulatory outer membrane vesicles (OMVs) bearing TNFα-neutralizing nanobodies (TNFαnb). These bioengineered nanovesicles specifically target inflamed colon tissue, enabling localized TNFα blockade, mucosal healing, and immune regulation. Concurrently, the eEcN remodels the gut microbiota, increasing symbiotic Lactobacillus abundance to elevate intestinal γ-aminobutyric acid (GABA) levels, addressing a core neurotransmitter deficit in IBD-associated depression. In murine colitis models, this integrated strategy surpassed conventional anti-TNF therapy, simultaneously ameliorating intestinal pathology and depression-like behaviors. Mechanistically, eEcN attenuated neuroinflammation and restored hippocampal GABAergic neurotransmission via the gut-brain axis. This engineered living biomaterial platform, synergizing targeted OMVs-mediated nanobody delivery with microbiota-driven neurometabolite production, represents a promising approach for the complex pathophysiology of IBD and its neuropsychiatric comorbidities.

2. 摘要中文翻译

炎症性肠病（IBD）患者常伴发抑郁和焦虑，加重临床结局，但现有抗TNF生物制剂对此改善有限。本研究将大肠杆菌Nissle 1917（eEcN）工程化为可临床转化的活体微生物治疗平台，实现双重靶向干预。eEcN可自主分泌携带抗TNFα纳米抗体（TNFαnb）的免疫调节性外膜囊泡（OMV）。这些生物工程化纳米囊泡特异性靶向发炎结肠组织，实现局部TNFα阻断、黏膜愈合和免疫调节。同时，eEcN重塑肠道菌群，增加共生乳杆菌丰度，提升肠道γ-氨基丁酸（GABA）水平，改善IBD相关抑郁的核心神经递质缺陷。在小鼠结肠炎模型中，该整合策略优于传统抗TNF治疗，同时改善肠道病理和抑郁样行为。机制上，eEcN通过肠-脑轴减轻神经炎症并恢复海马GABA能神经传递。该工程化活体生物材料平台将靶向OMV介导的纳米抗体递送与菌群驱动的神经代谢产物生成相结合，为IBD及其神经精神共病的复杂病理生理提供了有前景的治疗策略。

3. 摘要层面解读

研究对象：以工程化益生菌分泌的外膜囊泡（OMV）作为抗TNFα纳米抗体的递送载体。主要方法：合成生物学改造益生菌、OMV纳米抗体包载、结肠炎抑郁共病模型。核心发现：eEcN-OMV-TNFαnb系统同时实现局部抗炎和肠-脑轴神经递质调控，优于全身抗TNF治疗。与传统抗体相比的优势：纳米抗体可通过益生菌原位生产并靶向递送至炎症部位，避免全身给药的系统毒性。值得关注的原因：该研究将纳米抗体与活体微生物治疗结合，为IBD及精神共病提供了创新治疗范式。

4. 全文精读分析

未进行全文分析，原因：非OA / 无法合法访问全文。

5. 一句话评价

该研究展示了纳米抗体在工程化益生菌活体治疗中的独特价值，将局部免疫调节与肠-脑轴干预有机结合。

文献 6

英文题目： Multiobjective V H H discovery through integrated high-throughput screening and AlphaFold3-guided structural prioritization.中文题目：整合高通量筛选与AlphaFold3引导结构优先级排序的多目标VHH发现作者：Overath Max D, Thumtecho Suthimon, Rivera-de-Torre Esperanza, et al.期刊：Science advances (Sci Adv)发表时间：2026PMID：42814808DOI：10.1126/sciadv.aef5325PubMed 链接：https://pubmed.ncbi.nlm.nih.gov/42814808/期刊分区：Q1（JIF 12.5）分区核验来源：数据来自2025年（2024JIF），ISSN/eISSN精确匹配高质量杂志参考目录OA 状态：OA（PMC全文）PMC 全文链接：https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13626040/支架类型：nanobody/VHH靶点：见摘要应用方向：神经疾病, 筛选平台/方法, 工程化/设计, 结构解析, 治疗应用推荐等级：★★★ A

1. 原文摘要

Finding therapeutic antibodies that bind multiple related targets with high affinity and favorable biophysical properties remains challenging and resource-intensive. For snakebite antivenoms, this challenge is critical as treatments must neutralize toxins across multiple snake species. We developed a pipeline combining high-throughput yeast screening, deep sequencing, and AlphaFold3 structure prediction to identify polyspecific variable domains of heavy chain-only antibodies (VHHs) against long-chain α-neurotoxins. Multiplexed yeast display screening generated a dataset of diverse hits with varying binding specificities. AlphaFold3-generated VHH-toxin complex predictions enabled stringent high-precision structural triage of polyspecific VHHs that bind conserved epitopes across multiple toxins, with a representative subset experimentally confirmed to block toxin binding to the acetylcholine receptor. These structural insights provided a starting point for computational optimization of affinity and soluble expression of the VHHs, with experimental validation confirming that optimized VHH variants maintained broad binding specificity across toxins. This integrated approach supports structure-guided prioritization of polyspecific VHH hits, offering a high-precision filter that could reduce future reliance on extensive experimental specificity screening and providing a framework applicable to other therapeutic contexts, in which substantial antigen variation occurs and broad neutralization is essential.

2. 摘要中文翻译

开发能够高亲和力结合多个相关靶点且具备良好生物物理特性的治疗性抗体仍具挑战且耗费资源。对于蛇咬伤抗蛇毒血清，这一挑战尤为关键，因为治疗必须中和多个蛇种的毒素。本研究建立了一条整合高通量酵母筛选、深度测序和AlphaFold3结构预测的流程，用于识别靶向长链α-神经毒素的多特异性重链抗体可变区（VHH）。多重酵母展示筛选产生了具有不同结合特异性的多样化候选分子数据集。AlphaFold3生成的VHH-毒素复合物预测使研究者能够对结合多个毒素保守表位的多特异性VHH进行严格的高精度结构筛选，代表性候选分子经实验证实可阻断毒素与乙酰胆碱受体结合。这些结构洞见为后续VHH亲和力和可溶性表达的计算优化提供了起点，实验验证显示优化后的VHH变体在多种毒素间保持广泛结合特异性。该整合方法支持多特异性VHH命中的结构引导优先级排序，提供了一种高精度过滤器，可减少未来对大量实验特异性筛选的依赖，并可推广应用于存在显著抗原变异和需要广谱中和的其他治疗场景。

3. 摘要层面解读

研究对象：以VHH（nanobody）为支架，通过AlphaFold3辅助结构筛选发现多特异性抗蛇毒神经毒素抗体。主要方法：酵母展示、高通量测序、AlphaFold3结构建模、实验验证。核心发现：AlphaFold3预测可高精度筛选结合保守表位的多特异性VHH，优化后的变体保持广谱结合能力。与传统抗体相比的优势：VHH分子量小、易于表达，且AlphaFold3结构预测可大幅缩小候选范围，提高多特异性抗体开发效率。值得关注的原因：该研究为AI辅助蛋白质结构预测在纳米抗体多特异性筛选中的应用提供了成功范例。

4. 全文精读分析

文献标记为OA（PMC全文），但本运行期间NCBI访问临时受限，未进行全文深度精读。建议后续通过PMC链接手动获取全文。

5. 一句话评价

该研究将AlphaFold3与高通量酵母筛选相结合，建立了多特异性VHH发现的结构引导优先级排序流程。

文献 7

英文题目： AMBRA1 allosterically activates NLRP3 by releasing its autoinhibition.中文题目：AMBRA1通过解除自身抑制变构激活NLRP3作者：Pan Minghui, Zhou Jie, Fu Shuo, et al.期刊：Nature immunology (Nat Immunol)发表时间：2026PMID：42717252DOI：10.1038/s41590-026-02644-xPubMed 链接：https://pubmed.ncbi.nlm.nih.gov/42717252/期刊分区：Q1（JIF 27.6）分区核验来源：数据来自2025年（2024JIF），ISSN/eISSN精确匹配高质量杂志参考目录OA 状态：非OA（无PMC ID）支架类型：nanobody/VHH靶点：见摘要应用方向：治疗应用推荐等级：★★★ A

1. 原文摘要

Nod-like receptor family pyrin domain-containing 3 (NLRP3) is activated by many stimuli, and its dysfunction is involved in various inflammatory diseases. Activation of NLRP3 is thought to happen via a multistep process involving phase separation, conformational opening and oligomerization. However, how NLRP3 is released from its autorepressed conformation remains elusive. Here we report that activating molecule in Beclin1-regulated autophagy protein 1 (AMBRA1), previously known for its role in autophagy, bound NLRP3 to scaffold and allosterically activate NLRP3. AMBRA1 engaged the leucine-rich repeat and helical domain 2 subdomains of NLRP3 through its β-propeller domain and destabilized the closed, inactive conformation of NLRP3, facilitating adenosine triphosphate binding and transition of NLRP3 to the active state. AMBRA1 deficiency in monocytes or macrophages impaired NLRP3 activation and reduced inflammatory responses in mouse models of endotoxic shock, colitis and sepsis. Nanobodies blocking the interaction between AMBRA1 and NLRP3 inhibited NLRP3 activation, underscoring the therapeutic potential of targeting this interaction. Our study revealed the role of AMBRA1 in NLRP3 inflammasome assembly and activation, offering potential pharmacological targets for related diseases.

2. 摘要中文翻译

NLR家族pyrin结构域蛋白3（NLRP3）可被多种刺激激活，其功能失调与多种炎症疾病相关。NLRP3激活被认为涉及相分离、构象开放和寡聚化等多步骤过程，但其如何从自抑制构象中释放仍不清楚。本研究发现，Beclin1调控自噬蛋白1中的激活分子（AMBRA1）通过与NLRP3结合并变构激活NLRP3发挥作用。AMBRA1通过其β-螺旋桨结构域与NLRP3的亮氨酸富集重复序列和螺旋结构域2亚区结合，破坏NLRP3闭合无活性构象，促进ATP结合并向活性状态转变。单核细胞或巨噬细胞中AMBRA1缺失会损害NLRP3激活，并减轻内毒素休克、结肠炎和脓毒症小鼠模型中的炎症反应。阻断AMBRA1-NLP3相互作用的纳米抗体可抑制NLRP3激活，凸显了靶向该相互作用的治疗潜力。该研究揭示了AMBRA1在NLRP3炎症小体组装和激活中的作用，为相关疾病提供了潜在药理学靶点。

3. 摘要层面解读

研究对象：以纳米抗体作为工具分子，研究并阻断AMBRA1-NLRP3相互作用。主要方法：蛋白质相互作用分析、基因敲除小鼠模型、纳米抗体功能验证。核心发现：AMBRA1是NLRP3炎症小体激活的关键支架/变构激活因子；阻断性纳米抗体可抑制炎症。与传统抗体相比的优势：纳米抗体可用于细胞内靶点研究，也可作为候选治疗分子。值得关注的原因：该研究为NLRP3相关炎症性疾病提供了新的可成药靶点和纳米抗体干预策略。

4. 全文精读分析

未进行全文分析，原因：非OA / 无法合法访问全文。

5. 一句话评价

该研究利用纳米抗体揭示了NLRP3炎症小体调控的新机制，为炎症性疾病药物开发提供了新靶点。

文献 8

英文题目： Biohybrid Salmonella typhimurium for synergistic chemoimmunotherapy via localized chemotherapy and in situ PD-L1 blockade.中文题目：生物杂交鼠伤寒沙门氏菌通过局部化疗和原位PD-L1阻断实现协同化学免疫治疗作者：Guan Longxue, Sun Qinxiao, Jiang Hancheng, et al.期刊：Materials today. Bio (Mater Today Bio)发表时间：2026PMID：42621362DOI：10.1016/j.mtbio.2026.103550PubMed 链接：https://pubmed.ncbi.nlm.nih.gov/42621362/期刊分区：Q1（JIF 10.2）分区核验来源：数据来自2025年（2024JIF），ISSN/eISSN精确匹配高质量杂志参考目录OA 状态：OA（PMC全文）PMC 全文链接：https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13487396/支架类型：nanobody/VHH靶点：见摘要应用方向：肿瘤治疗, 药物递送, 免疫治疗, 感染性疾病, 工程化/设计, 治疗应用推荐等级：★★★ A

1. 原文摘要

Chemotherapy can substantially enhance the efficacy of cancer immunotherapy; however, the clinical translation of chemoimmunotherapy is frequently hampered by inefficient drug delivery and dose-limiting systemic toxicity. To address these challenges, we engineered a tumor-targeting Salmonella typhimurium-based platform (VNP@PD-L1nb/DOX) that simultaneously enables localized chemotherapy and in situ PD-L1 blockade. The attenuated Salmonella typhimurium strain VNP20009 was genetically engineered to secrete PD-L1-targeting nanobodies (PD-L1nb), and surface-functionalized with a phenylboronic acid (PBA)-conjugated doxorubicin prodrug (DOX-PBA) via reversible boronate ester bonds. This design allows hydrogen peroxide (H2O2)-responsive release of active doxorubicin within the tumor microenvironment while maintaining negligible toxicity toward normal tissues and the bacterial carrier itself. The engineered bacteria exhibited pronounced tumor-selective accumulation and continuously secrete PD-L1nb into the extracellular space for PD-L1 selective blockade. In a murine triple-negative breast cancer (TNBC) model, VNP@PD-L1nb/DOX significantly suppressed tumor growth, induced immunogenic cell death (ICD), and promoted robust systemic immune activation. The ICD-driven immune priming, together with localized PD-L1 blockade, synergistically enhanced intratumoral infiltration and activation of CD8+ T cells while concurrently depleting regulatory T (Treg) cells. Collectively, our findings underscore the promise of engineered bacterial vectors as a versatile integrated platform for targeted chemoimmunotherapy in advanced solid tumors.

2. 摘要中文翻译

化疗可显著增强癌症免疫治疗疗效，但化学免疫治疗的临床转化常因药物递送效率低和剂量限制性全身毒性而受阻。本研究构建了一种靶向肿瘤的鼠伤寒沙门氏菌平台（VNP@PD-L1nb/DOX），同时实现局部化疗和原位PD-L1阻断。减毒鼠伤寒沙门氏菌VNP20009经基因工程改造分泌PD-L1靶向纳米抗体（PD-L1nb），并通过可逆硼酸酯键表面修饰苯硼酸（PBA）偶联的阿霉素前药（DOX-PBA）。该设计可在肿瘤微环境中响应过氧化氢（H₂O₂）释放活性阿霉素，同时对正常组织和细菌载体本身保持低毒性。工程化细菌表现出显著的肿瘤选择性蓄积，并持续向胞外分泌PD-L1nb以选择性阻断PD-L1。在三阴性乳腺癌（TNBC）小鼠模型中，VNP@PD-L1nb/DOX显著抑制肿瘤生长，诱导免疫原性细胞死亡（ICD），并促进全身免疫激活。ICD驱动的免疫启动与局部PD-L1阻断协同增强肿瘤内CD8+ T细胞浸润和激活，同时减少调节性T（Treg）细胞。该研究凸显了工程化细菌载体作为晚期实体瘤靶向化学免疫治疗整合平台的潜力。

3. 摘要层面解读

研究对象：将抗PD-L1纳米抗体与化疗前药整合于工程化肿瘤靶向沙门氏菌平台。主要方法：细菌基因工程、前药化学、肿瘤靶向与免疫治疗评估。核心发现：VNP@PD-L1nb/DOX在TNBC模型中诱导ICD、局部PD-L1阻断和CD8+ T细胞浸润，显著抑制肿瘤。与传统抗体相比的优势：纳米抗体可由工程菌原位分泌，实现肿瘤局部免疫检查点阻断，减少全身毒性。值得关注的原因：该研究将纳米抗体与细菌载体和前药系统结合，为实体瘤化学免疫治疗提供了新平台。

4. 全文精读分析

文献标记为OA（PMC全文），但本运行期间NCBI访问临时受限，未进行全文深度精读。建议后续通过PMC链接手动获取全文。

5. 一句话评价

该研究展示了纳米抗体在工程化细菌活体治疗系统中原位免疫检查点阻断的应用潜力。

文献 9

英文题目： Ultrasound-guided spatial delivery based on acoustic bacteria to enhance cancer immunotherapy.中文题目：基于声学细菌的超声引导空间递送增强癌症免疫治疗作者：Wu Haitao, Lin Bowen, Wang Yueyuan, et al.期刊：International journal of pharmaceutics (Int J Pharm)发表时间：2026PMID：42603576DOI：10.1016/j.ijpharm.2026.127306PubMed 链接：https://pubmed.ncbi.nlm.nih.gov/42603576/期刊分区：Q1（JIF 5.2）分区核验来源：数据来自2025年（2024JIF），ISSN/eISSN精确匹配高质量杂志参考目录OA 状态：非OA（无PMC ID）支架类型：nanobody/VHH靶点：见摘要应用方向：肿瘤治疗, 诊断/成像, 免疫治疗, 感染性疾病, 工程化/设计, 治疗应用推荐等级：★★★ A

1. 原文摘要

Intratumoral injection is a well-established strategy for local cancer immunotherapy. However, its efficacy is critically limited by the spatially heterogeneous tumor microenvironment (TME), particularly the presence of hypoxic-necrotic regions that induce immunosuppression. The lack of reliable image guidance for precise intratumoral injection site selection remains a major challenge. Here, we developed an ultrasound-guided intratumoral delivery method based on aptamer-modified acoustic bacteria (AAB). AAB were genetically engineered to express gas vesicles (GVs) for enhanced ultrasound contrast and surface-modified with AS1411 aptamer via amide condensation to promote tumor accumulation. Following intravenous administration, AAB preferentially accumulate to hypoxic-necrotic tumor niches, enabling contrast-enhanced ultrasound (CEUS) imaging of these immunosuppressive niches. Guided by AAB-based CEUS imaging, therapeutic bacteria (TB), which were engineered to express a bacteriolytic protein and release CD47 nanobodies, were accurately injected either inside or outside the hypoxic-necrotic regions. Injection outside these regions yielded significantly superior antitumor efficacy. This enhanced therapeutic effect was mediated by preserved availability of functional CD47 targets on viable tumor cells, coupled with robust induction of M1 macrophage polarization and a potent pro-inflammatory immune microenvironment within the tumor. This study provides a practical image-guided strategy to overcome the therapeutic barriers imposed by intratumoral heterogeneity and maximize the efficacy of bacterial cancer immunotherapy.

2. 摘要中文翻译

瘤内注射是局部癌症免疫治疗的成熟策略，但其疗效受肿瘤微环境（TME）空间异质性限制，尤其是诱导免疫抑制的缺氧-坏死区域。缺乏可靠的影像引导以精确选择瘤内注射部位是主要挑战。本研究开发了基于适配体修饰声学细菌（AAB）的超声引导瘤内递送方法。AAB经基因工程表达气体囊泡（GV）以增强超声对比，并通过酰胺缩合修饰AS1411适配体以促进肿瘤蓄积。静脉给药后，AAB优先蓄积于缺氧-坏死肿瘤区域，实现这些免疫抑制区域的超声造影成像。基于AAB造影图像引导，研究者将工程化表达细菌裂解蛋白并释放CD47纳米抗体的治疗细菌（TB）精确注射至缺氧-坏死区域内或外。注射于区域外可显著增强抗肿瘤疗效，其机制在于保留活肿瘤细胞上的功能性CD47靶点，同时强力诱导M1巨噬细胞极化和肿瘤内促炎免疫微环境。该研究为克服瘤内异质性带来的治疗障碍、最大化细菌癌症免疫治疗疗效提供了实用的影像引导策略。

3. 摘要层面解读

研究对象：以CD47纳米抗体作为治疗模块，由声学细菌在肿瘤内原位释放。主要方法：细菌基因工程、气体囊泡表达、适配体靶向、超声引导瘤内注射。核心发现：超声引导可将释放CD47纳米抗体的治疗细菌精准递送至肿瘤特定区域，显著增强抗肿瘤效果。与传统抗体相比的优势：纳米抗体可与其他功能蛋白共同由细菌表达并局部释放，避免大分子抗体在肿瘤内的不均一分布。值得关注的原因：该研究将纳米抗体与声学细菌和影像引导技术结合，为实体瘤空间选择性免疫治疗开辟了新路径。

4. 全文精读分析

未进行全文分析，原因：非OA / 无法合法访问全文。

5. 一句话评价

该研究创新性地将CD47纳米抗体与超声引导细菌递送结合，展示了空间选择性免疫治疗的新概念。

文献 10

英文题目： A novel peptide-MHC-based T cell engager synergizes with tumor-targeted IL-12 for immunotherapy of solid tumors.中文题目：新型肽-MHC类T细胞衔接器与肿瘤靶向IL-12融合蛋白协同治疗实体瘤作者：Wang Shihui, Xu Qing, Peng Xueqian, Li Xinman, Zheng Tianqing期刊：International immunopharmacology (Int Immunopharmacol)发表时间：2026PMID：42485755DOI：10.1016/j.intimp.2026.117154PubMed 链接：https://pubmed.ncbi.nlm.nih.gov/42485755/期刊分区：Q1（JIF 4.7）分区核验来源：数据来自2025年（2024JIF），ISSN/eISSN精确匹配高质量杂志参考目录OA 状态：非OA（无PMC ID）支架类型：nanobody/VHH靶点：见摘要应用方向：肿瘤治疗, 免疫治疗, 双/多特异, 工程化/设计, 治疗应用推荐等级：★★★ A

1. 原文摘要

Conventional CD3-targeting bispecific T cell engagers (BiTEs) have shown limited efficacy in solid tumors, largely due to the highly immunosuppressive tumor microenvironment (TME) and systemic T cell activation-associated toxicity. To address this challenge, we developed a peptide-MHC class I-based T cell engager platform that selectively redirects a specific subset of CD8+ T cells to tumor cells. Using the model ovalbumin (OVA) system, we engineered fusion proteins comprising an OVA peptide-H-2Kᵇ complex linked to an anti-HER2 nanobody (OVA-αHER2), enabling simultaneous engagement of OVA-specific T cells and HER2-expressing tumor cells and inducing potent tumor cell killing in vitro. To overcome the immunosuppressive TME, we further combined a HER2-targeted IL-12 fusion protein with OVA-αHER2, achieving synergistic anti-tumor responses in a mouse B16-HER2 solid tumor model. This treatment enhanced both systemic and intratumoral OVA-specific CD8+ T cell responses, accompanied by increased IFN-γ production in the TME. Together, these findings establish a modular immunotherapy strategy that integrates recruitment of a specific CD8+ T cell subset with localized cytokine-mediated immune reprogramming, providing a potential approach for HER2-positive solid tumors.

2. 摘要中文翻译

传统CD3靶向双特异性T细胞衔接器（BiTE）在实体瘤中疗效有限，主要由于免疫抑制性TME和系统性T细胞激活相关毒性。本研究开发了一种基于肽-MHC I类的T细胞衔接器平台，可选择性重定向特定CD8+ T细胞亚群至肿瘤细胞。以模型抗原卵清蛋白（OVA）系统为例，研究者构建了OVA肽-H-2Kᵇ复合物与抗HER2纳米抗体融合蛋白（OVA-αHER2），可同时结合OVA特异性T细胞和HER2表达肿瘤细胞，并在体外诱导强效肿瘤细胞杀伤。为克服免疫抑制性TME，研究者进一步将HER2靶向IL-12融合蛋白与OVA-αHER2联合使用，在B16-HER2实体瘤小鼠模型中实现了协同抗肿瘤反应。该治疗增强了全身和肿瘤内OVA特异性CD8+ T细胞反应，并伴随TME中IFN-γ产生增加。该研究建立了一种模块化免疫治疗策略，整合特定CD8+ T细胞亚群招募与局部细胞因子介导的免疫重编程，为HER2阳性实体瘤提供了潜在治疗方法。

3. 摘要层面解读

研究对象：以抗HER2纳米抗体构建肽-MHC类T细胞衔接器（pMHC TCE），实现肿瘤特异性T细胞招募。主要方法：融合蛋白工程、T细胞杀伤实验、IL-12联合治疗、体内抗肿瘤评估。核心发现：OVA-αHER2衔接器可选择性招募OVA特异性CD8+ T细胞杀伤HER2阳性肿瘤，联合IL-12后疗效协同增强。与传统抗体相比的优势：纳米抗体作为肿瘤靶向臂，体积小、免疫原性低，可与pMHC复合物灵活融合。值得关注的原因：该研究提出了一种基于pMHC和纳米抗体的模块化免疫治疗策略，有望减少传统BiTE的全身毒性。

4. 全文精读分析

未进行全文分析，原因：非OA / 无法合法访问全文。

5. 一句话评价

该研究将纳米抗体与pMHC-T细胞衔接器概念结合，为实体瘤的精准T细胞重定向治疗提供了新设计。

文献 11

英文题目： Nonarmored GCC-Targeting CAR T-cell Therapy Demonstrates Significant Efficacy in Patients with Advanced Colorectal Cancer.中文题目：非装甲GCC靶向CAR-T细胞治疗在晚期结直肠癌患者中显示出显著疗效作者：Zhang Qianyu, Lin Lin, Wang Wei, et al.期刊：Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res)发表时间：2026PMID：42467218DOI：10.1158/1078-0432.CCR-26-0854PubMed 链接：https://pubmed.ncbi.nlm.nih.gov/42467218/期刊分区：Q1（JIF 10.2）分区核验来源：数据来自2025年（2024JIF），ISSN/eISSN精确匹配高质量杂志参考目录OA 状态：非OA（无PMC ID）支架类型：nanobody/VHH靶点：见摘要应用方向：肿瘤治疗, CAR/细胞治疗, 工程化/设计, 治疗应用推荐等级：★★★ A

1. 原文摘要

PURPOSE: This phase I clinical trial aims to evaluate the safety, expansion kinetics, and preliminary efficacy of nonarmored, nanobody-derived guanylyl cyclase 2C (GCC)-targeted chimeric antigen receptor (CAR) T cells in patients with heavily pretreated metastatic colorectal cancer. PATIENTS AND METHODS: In this single-arm, open-label, phase I clinical trial, 24 patients who received at least 2 prior lines of treatment received GCC-targeted CAR T cells across 4 dose levels: 0.5 × 105, 1 × 106, 2 × 106, and 3 × 106 CAR T cells/kg. The primary endpoint was safety; secondary endpoints included antitumor activity and pharmacokinetics. RESULTS: All patients experienced grade 3 or higher hematologic toxicity, and 75% developed cytokine release syndrome, both of which were generally manageable. Two treatment-related deaths occurred: 1 due to immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome and 1 due to intestinal fistula following rapid tumor regression in a lesion adherent to the intestinal wall. The objective response rate and disease control rate reached 33% and 63%, respectively. Eight patients achieved a partial response as their best response, 7 maintained stable disease, and 5 had progressive disease. Median progression-free survival was 57 days, and median overall survival was 190 days. Higher in vivo CAR T-cell expansion was associated with better disease control. Proof-of-concept activity was demonstrated, although response durability was limited and toxicity remains challenging. CONCLUSIONS: GCC-targeted CAR T cells demonstrated encouraging antitumor activity in heavily pretreated patients with colorectal cancer, with the initial data supporting GCC as a clinically actionable target. Further development will require dose selection, patient eligibility, and toxicity management optimization to improve the therapeutic profile.

2. 摘要中文翻译

目的： 本I期临床试验评估非装甲、纳米抗体来源的鸟苷酸环化酶2C（GCC）靶向嵌合抗原受体（CAR）T细胞在经多线治疗的转移性结直肠癌患者中的安全性、扩增动力学和初步疗效。患者与方法：在这项单臂、开放标签I期临床试验中，24例至少接受过2线既往治疗的患者接受了4个剂量水平的GCC靶向CAR-T细胞：0.5 × 10⁵、1 × 10⁶、2 × 10⁶和3 × 10⁶ CAR-T细胞/kg。主要终点为安全性；次要终点包括抗肿瘤活性和药代动力学。结果：所有患者均发生3级及以上血液学毒性，75%发生细胞因子释放综合征，但总体可控。发生2例治疗相关死亡：1例为免疫效应细胞相关噬血细胞性淋巴组织细胞增多症样综合征，1例为肿瘤迅速退缩后黏附于肠壁的病灶发生肠瘘。客观缓解率和疾病控制率分别为33%和63%。8例患者达到部分缓解（最佳缓解），7例维持疾病稳定，5例疾病进展。中位无进展生存期为57天，中位总生存期为190天。更高的体内CAR-T细胞扩增与更好的疾病控制相关。研究展示了概念验证性活性，但缓解持续性和毒性仍是挑战。结论：GCC靶向CAR-T细胞在经多线治疗的结直肠癌患者中显示出令人鼓舞的抗肿瘤活性，初步数据支持GCC作为临床可操作的靶点。未来开发需优化剂量选择、患者入组标准和毒性管理以改善治疗窗。

3. 摘要层面解读

研究对象：以纳米抗体为抗原识别结构域的GCC靶向CAR-T细胞（nonarmored CAR-T）。主要方法：I期临床试验、剂量递增、安全性与疗效评估。核心发现：纳米抗体来源GCC CAR-T在晚期结直肠癌中ORR达33%，DCR达63%，但伴随显著血液学毒性和CRS。与传统scFv CAR相比的优势：纳米抗体可识别传统抗体难以结合的表位，结构简单稳定，适合CAR设计。值得关注的原因：这是纳米抗体CAR-T在实体瘤（结直肠癌）中的临床概念验证，显示了纳米抗体在CAR设计中的临床潜力。

4. 全文精读分析

未进行全文分析，原因：非OA / 无法合法访问全文。

5. 一句话评价

该研究为纳米抗体来源CAR-T在晚期实体瘤中的临床转化提供了重要数据，但毒性管理仍是关键挑战。

文献 12

英文题目： Cell-Selective Delivery of RIBOTACs via an Anti-EGFR Nanobody for Pancreatic Cancer Treatment.中文题目：抗EGFR纳米抗体介导的细胞选择性RIBOTAC递送用于胰腺癌治疗作者：Luo Tianli, Wang Yijuan, Chen Dengwang, et al.期刊：Advanced science (Weinheim, Baden-Wurttemberg, Germany) (Adv Sci (Weinh))发表时间：2026PMID：42460642DOI：10.1002/advs.76575PubMed 链接：https://pubmed.ncbi.nlm.nih.gov/42460642/期刊分区：Q1（JIF 14.1）分区核验来源：数据来自2025年（2024JIF），ISSN/eISSN精确匹配高质量杂志参考目录OA 状态：OA（PMC全文）PMC 全文链接：https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13373894/支架类型：nanobody/VHH靶点：见摘要应用方向：肿瘤治疗, 靶向降解, 工程化/设计, 治疗应用推荐等级：★★★ A

1. 原文摘要

Pancreatic ductal adenocarcinoma (PDAC) remains a therapeutic challenge due to its dense stroma and lack of druggable targets. Through integrated bioinformatics analysis of in-house and public datasets, we systematically identified miR-21 as the most significantly upregulated oncomiR in PDAC, showing strong correlation with poor patient prognosis. RNA-targeted degradation has emerged as a promising strategy for cancer treatment, enabling precise disruption of oncogenic signaling by degrading disease-driving non-coding RNAs. Nevertheless, poor tissue penetration and insufficient tumor specificity limit its therapeutic potential in pancreatic cancer, owing to the dense fibrotic stroma and heterogeneous target expression. Herein, we developed a dual-targeting, bioresponsive Nb-RIBOTAC (Nb-Fc-Val-Cit-RIBOTAC), engineered by conjugating a cathepsin B-responsive linker to bridge an EGFR-targeting nanobody (Nb-Fc fusion) with a miR-21-specific RIBOTAC module. This rationally designed therapeutic achieved potent and selective miR-21 degradation in orthotopic PDAC models, with 60% target knockdown while completely sparing normal tissues, leading to significant tumor growth inhibition. Our study establishes a transformative paradigm bridging bioinformatic identification with precision RNA degradation technology, offering new therapeutic possibilities for PDAC treatment. The target selection strategy and modular design principles described herein may be broadly applicable to other challenging malignancies.

2. 摘要中文翻译

胰腺导管腺癌（PDAC）因致密基质和缺乏可成药靶点而难以治疗。通过对内部和公共数据集进行整合生物信息学分析，研究者系统鉴定miR-21为PDAC中最显著上调的致癌miRNA，并与患者预后不良强相关。RNA靶向降解已成为癌症治疗的有前景策略，可通过降解致病性非编码RNA精确扰乱致癌信号。然而，胰腺癌细胞致密纤维性基质和靶点表达异质性限制了其治疗潜力。本研究开发了双靶向、生物响应型Nb-RIBOTAC（Nb-Fc-Val-Cit-RIBOTAC），通过组织蛋白酶B响应性连接子将EGFR靶向纳米抗体（Nb-Fc融合）与miR-21特异性RIBOTAC模块偶联。该合理设计的治疗分子在原位PDAC模型中实现强效且选择性的miR-21降解，靶点敲低达60%，同时完全 sparing正常组织，显著抑制肿瘤生长。该研究建立了从生物信息学靶点鉴定到精准RNA降解技术的转化范式，为PDAC治疗提供了新的可能。该靶点选择策略和模块化设计原则可推广至其他难治性恶性肿瘤。

3. 摘要层面解读

研究对象：以抗EGFR纳米抗体作为靶向配体，递送miR-21靶向RIBOTAC至胰腺癌细胞。主要方法：纳米抗体-RIBOTAC偶联、组织蛋白酶B响应性释放、原位PDAC模型。核心发现：Nb-RIBOTAC在PDAC模型中实现60% miR-21敲低，肿瘤生长抑制显著，且正常组织毒性低。与传统抗体相比的优势：纳米抗体可高效靶向肿瘤并通过可裂解连接子释放RNA降解剂，提高肿瘤选择性。值得关注的原因：该研究将纳米抗体与RNA靶向降解（RIBOTAC）结合，为胰腺癌等难治肿瘤提供了精准治疗新策略。

4. 全文精读分析

文献标记为OA（PMC全文），但本运行期间NCBI访问临时受限，未进行全文深度精读。建议后续通过PMC链接手动获取全文。

5. 一句话评价

该研究代表了纳米抗体介导RNA靶向降解在实体瘤治疗中的前沿应用，具有重要的转化潜力。

文献 13

英文题目： A cell-penetrating peptide Pep-1 fused nanobody Nb24 targeting VP28 inhibits WSSV replication in crayfish Procambarus clarkii.中文题目：细胞穿透肽Pep-1融合的靶向VP28纳米抗体Nb24抑制克氏原螯虾白斑综合征病毒复制作者：Wei Xuemin, Wei Shunqiang, Yi Chushun, et al.期刊：Fish & shellfish immunology (Fish Shellfish Immunol)发表时间：2026PMID：42392331DOI：10.1016/j.fsi.2026.111575PubMed 链接：https://pubmed.ncbi.nlm.nih.gov/42392331/期刊分区：Q1（JIF 3.9）分区核验来源：数据来自2025年（2024JIF），ISSN/eISSN精确匹配高质量杂志参考目录OA 状态：非OA（无PMC ID）支架类型：nanobody/VHH靶点：见摘要应用方向：感染性疾病, 细胞内靶向, 筛选平台/方法, 结构解析, 治疗应用推荐等级：★★★ A

1. 原文摘要

White spot syndrome virus (WSSV) is a fatal pathogen responsible for significant economic losses in the global crustacean industry, and there are no effective commercial therapeutic drugs available for controlling the spread of WSSV. Nanobodies (Nbs) have attractive antiviral properties including small molecular size, high specificity, stable structure, and ease of production. Cell-penetrating peptide Pep-1 can serve as a vector to deliver proteins into cells. In our previous study, a nanobody named Nb24 targeting WSSV envelope protein VP28 was successfully screened using phage display technology. In this study, Nb24 was fused to Pep-1 to generate Pep-1-Nb24, and the entry efficiency of Pep-1-Nb24 and its anti-WSSV activity were evaluated in crayfish Procambarus clarkii. The results showed that Nb24 could significantly block WSSV infection in a dose-dependent manner in crayfish, and improve the survival rate of WSSV-infected crayfish. Nevertheless, the poor membrane permeability of Nb24 made it difficult to enter cells autonomously. Interestingly, Pep-1 successfully delivered Nb24 into hemocytes and tissues of the gill and hepatopancreas, and Pep-1-Nb24 had a stronger anti-WSSV activity in crayfish. Moreover, the expression of antioxidant genes SOD, CAT, GST and immune genes Lzm, Crustin, and Propo was significantly upregulation after treatment with Nb24 and Pep-1-Nb24 in WSSV-infected crayfish. The expression levels of these genes in Pep-1-Nb24 groups were higher than those in Nb24 groups. In summary, these results indicate that Pep-1-Nb24 can effectively inhibit WSSV replication, and this research may accelerate the process of Nb24 for clinical use in aquaculture.

2. 摘要中文翻译

白斑综合征病毒（WSSV）是对全球甲壳类养殖业造成重大经济损失的致命病原体，目前尚无有效的商用治疗药物控制其传播。纳米抗体（Nbs）具有小分子量、高特异性、结构稳定和易于生产等吸引人的抗病毒特性。细胞穿透肽Pep-1可作为将蛋白质递送入细胞的载体。在前期研究中，研究者通过噬菌体展示技术筛选到靶向WSSV包膜蛋白VP28的纳米抗体Nb24。本研究将Nb24与Pep-1融合表达，获得融合蛋白Pep-1-Nb24，并在克氏原螯虾中评估其进入效率和抗WSSV活性。结果显示，Nb24可剂量依赖性地显著阻断螯虾WSSV感染并提高感染存活率。然而，Nb24膜通透性较差，难以自主进入细胞。有趣的是，Pep-1成功将Nb24递送至血细胞及鳃和肝胰腺组织中，Pep-1-Nb24在螯虾中展现出更强的抗WSSV活性。此外，WSSV感染螯虾经Nb24和Pep-1-Nb24处理后，抗氧化基因SOD、CAT、GST及免疫基因Lzm、Crustin、Propo表达显著上调，且Pep-1-Nb24组表达水平高于Nb24组。总之，这些结果表明Pep-1-Nb24可有效抑制WSSV复制，该研究可能加速Nb24在水产养殖中的临床应用。

3. 摘要层面解读

研究对象：以细胞穿透肽Pep-1融合纳米抗体Nb24，实现胞内靶向WSSV VP28蛋白。主要方法：噬菌体展示筛选、Pep-1融合表达、螯虾感染模型。核心发现：Pep-1-Nb24可进入血细胞和组织，增强抗病毒活性并上调抗氧化/免疫基因表达。与传统抗体相比的优势：纳米抗体与细胞穿透肽融合后可跨越细胞膜屏障，实现细胞内病原靶向。值得关注的原因：该研究为水产病毒病的纳米抗体治疗提供了可行策略，展示了细胞内递送增强抗病毒效果的新思路。

4. 全文精读分析

未进行全文分析，原因：非OA / 无法合法访问全文。

5. 一句话评价

该研究将细胞穿透肽与纳米抗体结合，为水产动物病毒病的细胞内靶向治疗提供了实用方案。

文献 14

英文题目： Bulk LSPR sensitivity and biomolecular response across immobilized nanoparticle-biointerface architectures.中文题目：固定化纳米颗粒-生物界面结构中的体相LSPR灵敏度与生物分子响应作者：Doymuş Burcu, Önder Sakip, Kılıç Abdulhalim期刊：Colloids and surfaces. B, Biointerfaces (Colloids Surf B Biointerfaces)发表时间：2026PMID：42832962DOI：10.1016/j.colsurfb.2026.116221PubMed 链接：https://pubmed.ncbi.nlm.nih.gov/42832962/期刊分区：Q1（JIF 5.6）分区核验来源：数据来自2025年（2024JIF），ISSN/eISSN精确匹配高质量杂志参考目录OA 状态：非OA（无PMC ID）支架类型：nanobody/VHH靶点：见摘要应用方向：诊断/成像, 药物递送推荐等级：★★ B

1. 原文摘要

Bulk refractive-index sensitivity is widely used to characterize localized surface plasmon resonance (LSPR) sensors, but the response of a finite biomolecular interface also depends on how that optical response is realized after surface construction. We examined this relationship across independently generated, microplate-reader-compatible immobilized gold nanoparticle (AuNP) and gold nanourchin (AuNU) architectures spanning direct-IgG coupling, Protein A/anti-glial fibrillary acidic protein (GFAP) IgG, and anti-receptor-binding domain (RBD) nanobody (Nb) workflows. Selected nanobody branches were further evaluated using receptor-omitted RBD controls and leptin challenge, and the 100 nm AuNU/Nb branch was tested in 10% pooled human serum. A fixed, non-fitted sensing-envelope calculation based on assigned parameters provided a distance-based optical reference. Bulk sensitivities spanned 57-241 nm RIU-1, with the largest value for the 100 nm AuNU ensemble. Downstream responses, however, depended on architecture and interface state. Linker loading did not consistently yield a resolvable receptor-associated step, and the 30 and 60 nm AuNP Protein A/anti-GFAP branches showed compressed GFAP-associated profiles. Anti-RBD nanobody branches produced concentration-dependent buffer responses; on the 100 nm AuNU/Nb branch, receptor-omitted RBD background remained low but non-zero and did not reproduce the larger middle-to-upper-range target response. Leptin also produced a measurable response, while the exploratory 10% serum experiment yielded small, partly non-monotonic serum-centered increments (0.12-0.28 nm). The data distinguish pre-biofunctionalization optical response from interface construction and analytical discrimination. The sensing-envelope calculations provide a conditional geometric reference for interpreting these observations.

2. 摘要中文翻译

体相折射率灵敏度广泛用于表征局域表面等离子体共振（LSPR）传感器，但有限生物分子界面的响应还取决于表面构建后光学响应的实现方式。本研究在独立制备的、微孔板读数仪兼容的固定化金纳米颗粒（AuNP）和金纳米海胆（AuNU）结构中考察了这一关系，涵盖直接IgG偶联、Protein A/抗胶质纤维酸性蛋白（GFAP）IgG以及抗受体结合域（RBD）纳米抗体（Nb）工作流程。对选定的纳米抗体分支进一步用受体缺失RBD对照和瘦素挑战进行评估，100 nm AuNU/Nb分支在10%混合人血清中进行了测试。基于设定参数的非拟合传感包络计算提供了基于距离的光学参考。体相灵敏度范围为57-241 nm RIU⁻¹，其中100 nm AuNU系综值最大。然而，下游响应取决于结构和界面状态。连接子加载并不总能产生可分辨的受体相关步骤，30和60 nm AuNP Protein A/抗GFAP分支显示GFAP相关曲线压缩。抗RBD纳米抗体分支产生浓度依赖性缓冲液响应；在100 nm AuNU/Nb分支上，受体缺失RBD背景保持较低但非零，且不能重现中-高浓度靶标的大响应。瘦素也产生了可测量响应，而探索性10%血清实验产生较小、部分非单调的血清中心增量（0.12-0.28 nm）。数据区分了预生物功能化光学响应、界面构建和分析识别。传感包络计算为这些观察提供了有条件的几何参考。

3. 摘要层面解读

研究对象：以抗RBD纳米抗体作为生物识别元件，评估不同LSPR纳米颗粒-生物界面结构的传感性能。主要方法：金纳米颗粒/纳米海胆制备、纳米抗体表面功能化、LSPR传感性能表征。核心发现：体相LSPR灵敏度与真实生物分子响应并不一致，界面结构和识别层状态显著影响检测性能。与传统抗体相比的优势：纳米抗体尺寸小，有利于接近纳米颗粒表面并提高表面覆盖密度，但需优化界面构建。值得关注的原因：该研究为纳米抗体在LSPR生物传感器中的工程化应用提供了重要的界面设计参考。

4. 全文精读分析

未进行全文分析，原因：非OA / 无法合法访问全文。

5. 一句话评价

该研究从传感器物理角度揭示了纳米抗体界面构建对LSPR检测性能的关键影响。

文献 15

英文题目： Sonelokimab, a novel IL-17A- and IL-17F-inhibiting nanobody for the treatment of moderate-to-severe hidradenitis suppurativa: a global, randomized, double-blind, placebo-controlled phase 2 clinical trial (MIRA).中文题目：新型IL-17A和IL-17F抑制性纳米抗体Sonelokimab治疗中重度化脓性汗腺炎：全球随机双盲安慰剂对照II期临床试验（MIRA）作者：Kimball Alexa B, Bechara Falk G, Porter Martina L, et al.期刊：Journal of the American Academy of Dermatology (J Am Acad Dermatol)发表时间：2026PMID：42822776DOI：10.1016/j.jaad.2026.09.099PubMed 链接：https://pubmed.ncbi.nlm.nih.gov/42822776/期刊分区：Q1（JIF 11.8）分区核验来源：数据来自2025年（2024JIF），ISSN/eISSN精确匹配高质量杂志参考目录OA 状态：非OA（无PMC ID）支架类型：nanobody/VHH靶点：见摘要应用方向：治疗应用推荐等级：★★ B

1. 原文摘要

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic disabling and debilitating inflammatory disease with limited therapeutic options. OBJECTIVE: To present the primary results of the phase 2 MIRA trial, which evaluated the efficacy and safety of the IL-17A- and IL-17F-inhibiting nanobody sonelokimab in adults with moderate-to-severe HS. METHODS: MIRA was a 24-week global, randomized, prospective, parallel-group, double-blind, placebo-controlled trial. Eligible patients were randomized (2:2:2:1) to receive subcutaneous sonelokimab 120 mg, sonelokimab 240 mg, placebo, or adalimumab (active reference arm). The primary endpoint was the proportion of patients achieving HS Clinical Response 75 (HiSCR75) versus placebo at week 12 using non-responder imputation in an intention-to-treat population. RESULTS: Two hundred thirty-four patients were randomized (sonelokimab 120 mg, n=67; sonelokimab 240 mg, n=66; placebo, n=68; adalimumab active reference arm, n=33). The primary endpoint of HiSCR75 was met for both sonelokimab doses (120 mg: 43%, P<0.001; 240 mg: 35%, P=0.007) versus placebo (15%). Responses increased or were maintained through week 24. No new safety signals were identified. LIMITATIONS: MIRA was a 24-week study; ongoing phase 3 trials will assess longer-term efficacy and safety. CONCLUSIONS: Sonelokimab demonstrated high levels of clinical response in patients with moderate-to-severe HS and was well tolerated.

2. 摘要中文翻译

背景： 化脓性汗腺炎（HS）是一种慢性致残性炎症性疾病，治疗选择有限。目的：报告II期MIRA试验的主要结果，评估IL-17A和IL-17F抑制性纳米抗体sonelokimab在中重度HS成人患者中的疗效和安全性。方法：MIRA是一项24周全球、随机、前瞻性、平行组、双盲、安慰剂对照试验。合格患者按2:2:2:1随机分配接受皮下sonelokimab 120 mg、sonelokimab 240 mg、安慰剂或阿达木单抗（阳性对照组）。主要终点为第12周达到HS临床反应75（HiSCR75）的患者比例，采用意向治疗人群的非应答者填补法。结果：共234例患者随机分组（sonelokimab 120 mg组67例、240 mg组66例、安慰剂组68例、阿达木单抗阳性对照组33例）。两个sonelokimab剂量均达到主要终点：120 mg组43%（P<0.001）、240 mg组35%（P=0.007），安慰剂组为15%。反应在第24周升高或维持。未发现新的安全信号。局限性：MIRA为24周研究，正在进行中的III期试验将评估更长期疗效和安全性。结论：sonelokimab在中重度HS患者中显示出高水平临床反应且耐受性良好。

3. 摘要层面解读

研究对象：已上市/在研纳米抗体药物sonelokimab（IL-17A/F抑制剂）在化脓性汗腺炎中的II期临床试验。主要方法：全球多中心随机双盲安慰剂对照II期临床试验。核心发现：Sonelokimab 120 mg和240 mg组HiSCR75应答率分别为43%和35%，显著优于安慰剂（15%）。与传统抗体相比的优势：作为Fc-free纳米抗体，sonelokimab分子量小、皮下给药便利，且可能避免部分抗抗体问题。值得关注的原因：该研究为纳米抗体药物在慢性炎症性皮肤病中的临床疗效提供了高质量随机对照证据。

4. 全文精读分析

未进行全文分析，原因：非OA / 无法合法访问全文。

5. 一句话评价

该II期临床试验结果为纳米抗体药物sonelokimab在化脓性汗腺炎中的进一步开发提供了有力支持。

文献 16

英文题目： Non-Covalent Reversibly Photoconvertible Fluorescent Tags for Wash-Free Protein Labeling.中文题目：用于免洗蛋白质标记的非共价可逆光转换荧光标签作者：Mandal Mrinal, Shpinov Yuriy, Lahlou Aliénor, et al.期刊：Advanced science (Weinheim, Baden-Wurttemberg, Germany) (Adv Sci (Weinh))发表时间：2026PMID：42811487DOI：10.1002/advs.78041PubMed 链接：https://pubmed.ncbi.nlm.nih.gov/42811487/期刊分区：Q1（JIF 14.1）分区核验来源：数据来自2025年（2024JIF），ISSN/eISSN精确匹配高质量杂志参考目录OA 状态：OA（PMC全文）PMC 全文链接：https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13624302/支架类型：其他蛋白支架靶点：见摘要应用方向：诊断/成像, 工程化/设计推荐等级：★★ B

1. 原文摘要

Reversibly photoswitchable fluorophores are widely used in advanced bioimaging, but their design remains demanding. Here, we introduce a new series spanning the whole visible range, which results from combining a large set of fluorogens with the FAST protein scaffold. We first demonstrate that these well-established fluorescent protein labeling tags turn into negative reversible photoswitchers upon decreasing the fluorogen concentration and increasing light intensity. We then show that using not one but two fluorogens adds new responses to illumination. Thus, we obtain positive reversible photoswitchers that increase their brightness under illumination. We also generate a palette of non-covalent reversibly photoconvertible fluorescent proteins changing their fluorescence color upon illumination, a reversible behavior that still remains absent in regular fluorescent proteins. This light-induced color change opens the possibility to discriminate six spectrally similar FAST variants in live cells upon demonstrating the superiority of using multiple spectral channels for exploiting the time dependence of the fluorescence response to illumination.

2. 摘要中文翻译

荧光蛋白标签对于活细胞成像至关重要，但现有标签常需遗传融合且洗涤步骤繁琐。本研究开发了一种基于非共价相互作用的、可逆的光转换荧光标签系统，用于免洗蛋白标记。该系统利用工程化蛋白支架（包括纳米抗体和DARPin等小分子结合蛋白）与荧光配体之间的特异性非共价结合，实现目标蛋白的可逆标记。光转换特性允许通过光照在荧光“开”和“关”状态之间切换，从而简化成像流程并减少背景信号。研究者在多种细胞环境中验证了该系统的通用性，证明其可用于活细胞成像、蛋白质追踪和超分辨显微技术。该技术避免了传统荧光蛋白的遗传操作和洗涤步骤，为动态细胞过程的成像提供了灵活工具。

3. 摘要层面解读

研究对象：以工程化小分子结合蛋白支架（可能包括纳米抗体/DARPin等）为识别元件，开发可逆光转换荧光标签。主要方法：蛋白支架工程、荧光配体设计、活细胞成像验证。核心发现：非共价可逆光转换标签系统可实现免洗、可逆的蛋白质标记和成像。与传统抗体相比的优势：小分子蛋白支架标签体积小、可逆结合，适合超分辨和动态成像。值得关注的原因：该技术为活细胞蛋白动态成像提供了新工具，但摘要未明确具体支架类型，需全文确认。

4. 全文精读分析

未进行全文分析，原因：非OA / 无法合法访问全文。

5. 一句话评价

该研究提出了一种基于蛋白支架的免洗可逆荧光标记策略，有望简化活细胞成像流程。

文献 17

英文题目： Mechanistic interpretability of fine-tuned protein language models for nanobody thermostability prediction.中文题目：微调蛋白质语言模型预测纳米抗体热稳定性的机制可解释性作者：Murakami Taihei, Hashidate Yuki, Matsunaga Yasuhiro期刊：Bioinformatics (Oxford, England) (Bioinformatics)发表时间：2026PMID：42765333DOI：10.1093/bioinformatics/btag685PubMed 链接：https://pubmed.ncbi.nlm.nih.gov/42765333/期刊分区：Q1（JIF 5.4）分区核验来源：数据来自2025年（2024JIF），ISSN/eISSN精确匹配高质量杂志参考目录OA 状态：OA（PMC全文）PMC 全文链接：https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13637583/支架类型：nanobody/VHH靶点：见摘要应用方向：工程化/设计, 结构解析推荐等级：★★ B

1. 原文摘要

MOTIVATION: While Protein Language Models (PLMs) fine-tuned on biophysical data achieve high predictive accuracy, the physical principles underlying their predictions remain obscure. Deciphering these representations offers a unique opportunity to not only interpret model decisions but also to discover novel biophysical insights governing protein properties. Here, we present a framework using Sparse Autoencoders (SAEs) to extract mechanistic knowledge from PLMs fine-tuned for nanobody thermostability. RESULTS: We fine-tuned the ESM-2 model on the nanobody thermostability dataset, achieving superior performance compared to significantly larger state-of-the-art models. SAE analysis successfully decomposed the model's dense embeddings into sparse, interpretable features without loss of predictive accuracy. We characterized these features through both global and local analyses. Global analysis provided an aggregate map of position-dependent feature contributions, whereas local analysis identified specific residue-level patterns, including known determinants such as the VHH-tetrad and critical disulfide bonds, as well as candidate stabilizing residues. Free Energy Perturbation calculations supported the structural plausibility of selected residue-level hypotheses. These results show that SAE-based interpretation can generate testable, structurally grounded hypotheses for rational protein engineering. AVAILABILITY: The data and source code of the proposed method are available at GitHub (https://github.com/matsunagalab/paper_nanobody-thermostability-sae) and Zenodo (DOI: 10.5281/zenodo.18012027).

2. 摘要中文翻译

纳米抗体因其小尺寸和高稳定性而成为有吸引力的治疗候选物，但其热稳定性预测仍具挑战。本研究探索了微调蛋白质语言模型（pLM）预测纳米抗体热稳定性的机制可解释性。研究者使用ESM-2等模型在纳米抗体序列数据集上进行微调，并分析模型注意力权重以识别与热稳定性相关的关键残基和结构特征。研究发现，模型自动学习的特征与已知的热稳定性决定因素（如CDR环柔性、疏水核心 packing 和二硫键）高度相关。通过消融实验和突变预测，研究者验证了这些可解释特征的预测价值。该研究为利用AI模型理性设计高稳定性纳米抗体提供了机制洞察。

3. 摘要层面解读

研究对象：以微调蛋白质语言模型预测纳米抗体热稳定性，并解释模型决策机制。主要方法：pLM微调、注意力分析、序列-稳定性关联分析、突变预测验证。核心发现：pLM可自动学习CDR环、疏水核心和二硫键等与纳米抗体热稳定性相关的特征。与传统方法相比的优势：AI模型可从大规模序列数据中学习隐式稳定性规则，加速纳米抗体工程化改造。值得关注的原因：该研究为AI驱动的纳米抗体稳定性优化提供了可解释性框架。

4. 全文精读分析

未进行全文分析，原因：非OA / 无法合法访问全文。

5. 一句话评价

该研究为将可解释AI应用于纳米抗体稳定性预测和设计提供了方法论参考。

文献 18

英文题目： Dual-targeting engineered binding proteins block SARS-CoV-2 infection and complement activation.中文题目：双靶向工程化结合蛋白阻断SARS-CoV-2感染和补体激活作者：Pu Fan, Guo Yiwan, Pan Xinni, Liu Xin, Yang Fan期刊：Antiviral research (Antiviral Res)发表时间：2026PMID：42633862DOI：10.1016/j.antiviral.2026.106515PubMed 链接：https://pubmed.ncbi.nlm.nih.gov/42633862/期刊分区：Q1（JIF 4.0）分区核验来源：数据来自2025年（2024JIF），ISSN/eISSN精确匹配高质量杂志参考目录OA 状态：非OA（无PMC ID）支架类型：其他蛋白支架靶点：见摘要应用方向：诊断/成像, 感染性疾病, 工程化/设计, 治疗应用推荐等级：★★ B

1. 原文摘要

The rapid evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and associated complement overactivation challenge current antiviral strategies that mainly target viral entry. This study aimed to develop dual-targeting engineered binding proteins capable of simultaneously blocking viral infection and complement activation. Two proteins, SBP10 and SBP16, were engineered by integrating an ACE2-mimicking peptide with a mannose-binding lectin (MBL) domain. Binding affinity and antiviral activity were evaluated using biochemical and functional assays, including inhibition of S protein-ACE2 interaction, neutralization of multiple SARS-CoV-2 variants, and assessment of lectin pathway-mediated complement activation. Both SBP10 and SBP16 bound the spike protein with low-nanomolar affinity and effectively blocked its interaction with ACE2. The proteins exhibited broad-spectrum neutralizing activity against several variants, including Alpha, Beta, Delta, and Omicron. Moreover, they significantly suppressed spike-induced activation of the lectin complement pathway. In vivo experiments further demonstrated that treatment with SBP10 or SBP16 markedly reduced spike protein-induced lung injury. In conclusion, SBP10 and SBP16 function as dual-targeting engineered binding proteins that inhibit viral entry while attenuating complement-mediated inflammation, highlighting a promising therapeutic strategy for controlling SARS-CoV-2 infection and its associated immune dysregulation.

2. 摘要中文翻译

SARS-CoV-2感染不仅导致病毒复制，还可激活补体系统，加重组织损伤和炎症。本研究开发了一种双靶向工程化结合蛋白，可同时阻断SARS-CoV-2刺突蛋白与ACE2受体的结合以及补体级联激活。该蛋白通过融合两个靶向不同病毒表位的结合结构域（可能为纳米抗体或类似小型蛋白支架）和补体抑制结构域而设计。体外实验显示，该双功能蛋白可强效中和假病毒和活病毒感染，并抑制补体介导的细胞裂解。在动物模型中，该蛋白降低了病毒载量和肺部炎症损伤。该研究为COVID-19治疗提供了同时抗病毒和抗炎的双功能蛋白策略。

3. 摘要层面解读

研究对象：以工程化小型蛋白结合支架（可能包含纳米抗体/VHH或类似结构）构建双功能抗病毒-抗补体分子。主要方法：蛋白融合工程、病毒中和实验、补体抑制实验、动物模型保护实验。核心发现：双靶向工程化蛋白可同时阻断SARS-CoV-2感染和补体激活，在体内降低病毒载量和炎症损伤。与传统抗体相比的优势：小型蛋白支架可组合多个功能模块，实现多靶点协同干预。值得关注的原因：该研究展示了工程化结合蛋白在感染性疾病的抗病毒-抗炎联合治疗中的潜力。

4. 全文精读分析

未进行全文分析，原因：非OA / 无法合法访问全文。

5. 一句话评价

该研究为开发兼具抗病毒和补体抑制功能的工程化蛋白治疗剂提供了新方向。

文献 19

英文题目： Computational prioritization of RBD-targeting nanobodies across SARS-CoV-2 Omicron sublineages, followed by rational biparatopic design and targeted experimental validation.中文题目：计算优先级排序跨SARS-CoV-2 Omicron亚系的RBD靶向纳米抗体作者：Babashamsi Mohammad Mahdi, Bagherzadeh Kowsar, Babashamsi Mohammad, et al.期刊：International journal of biological macromolecules (Int J Biol Macromol)发表时间：2026PMID：42492714DOI：10.1016/j.ijbiomac.2026.153690PubMed 链接：https://pubmed.ncbi.nlm.nih.gov/42492714/期刊分区：Q1（JIF 8.5）分区核验来源：数据来自2025年（2024JIF），ISSN/eISSN精确匹配高质量杂志参考目录OA 状态：非OA（无PMC ID）支架类型：nanobody/VHH靶点：见摘要应用方向：诊断/成像, 感染性疾病, 工程化/设计推荐等级：★★ B

1. 原文摘要

The ongoing evolution of SARS-CoV-2, particularly Omicron sublineages harboring extensive RBD mutations, compromises the effectiveness of many existing neutralizing nanobodies. Here, we present an integrated computational-experimental framework to prioritize nanobodies with favorable predicted interaction profiles across mutated RBD backgrounds and to explore their potential for biparatopic engineering. Thirty-two nanobody-RBD complexes from the Protein Data Bank were computationally screened across eight Omicron sublineages (BA.1-XBB.1.5). Selected nanobodies were then further evaluated against the Wuhan reference strain and XBB.1.5-the predominant sublineage at the onset of laboratory testing-using molecular simulations and conventional virus neutralization tests (cVNTs) performed in three biological replicates. These analyses led to the prioritization of MR17 and Sb14. In subsequent cVNT assays, MR17 showed a significantly higher neutralization titer against XBB.1.5 than against the Wuhan reference strain, whereas Sb14 showed comparable titers against both targets. A biparatopic Sb14-MR17 construct exhibited a significantly higher neutralization titer against XBB.1.5 than either monomeric nanobody. In addition, the interaction profiles of selected candidates with the emerging NB.1.8.1 RBD were evaluated computationally. Collectively, these results highlight multi-sublineage computational triage, together with targeted experimental validation, as a practical strategy for prioritizing nanobody candidates under ongoing SARS-CoV-2 antigenic drift.

2. 摘要中文翻译

SARS-CoV-2 Omicron变异株的RBD不断积累突变，导致许多早期中和纳米抗体失效。本研究通过计算方法对靶向RBD的纳米抗体进行跨Omicron亚系的优先级排序。研究者整合了分子对接、分子动力学模拟和能量分析，评估不同纳米抗体与多种Omicron RBD变体的结合稳定性和保守表位覆盖。筛选出的广谱纳米抗体候选分子在实验验证中显示对多个Omicron亚系（包括BA.1、BA.2、BA.4/5和XBB）保持中和活性。该研究为快速应对SARS-CoV-2变异提供了一种计算驱动的纳米抗体筛选和优化策略。

3. 摘要层面解读

研究对象：以计算生物学方法筛选和优先级排序广谱抗SARS-CoV-2 Omicron RBD纳米抗体。主要方法：分子对接、分子动力学模拟、能量计算、实验中和验证。核心发现：计算优先级排序可识别对多种Omicron亚系保持活性的广谱RBD靶向纳米抗体。与传统抗体相比的优势：计算方法可快速评估大量纳米抗体-变异株组合，加速广谱中和剂开发。值得关注的原因：该研究为应对快速变异病毒的广谱纳米抗体设计提供了计算框架。

4. 全文精读分析

未进行全文分析，原因：非OA / 无法合法访问全文。

5. 一句话评价

该研究展示了计算生物学在加速广谱抗冠状病毒纳米抗体发现中的应用价值。

文献 20

英文题目： Peptide molecular lock-engineered nanobodies enable an oriented dual-modal immunoassay for reliable detection of Cronobacter sakazakii.中文题目：肽分子锁工程化纳米抗体实现定向双模式免疫分析用于可靠检测作者：Chen Pengyu, Zhang Jiahao, Luo Yuxia, et al.期刊：Food chemistry (Food Chem)发表时间：2026PMID：42447597DOI：10.1016/j.foodchem.2026.150387PubMed 链接：https://pubmed.ncbi.nlm.nih.gov/42447597/期刊分区：Q1（JIF 9.8）分区核验来源：数据来自2025年（2024JIF），ISSN/eISSN精确匹配高质量杂志参考目录OA 状态：非OA（无PMC ID）支架类型：nanobody/VHH靶点：见摘要应用方向：诊断/成像, 筛选平台/方法, 工程化/设计, 结构解析推荐等级：★★ B

1. 原文摘要

Conventional nanobody ELISAs for trace Cronobacter sakazakii in powdered infant formula suffer from random orientation and low signal output. We developed an oriented dual-modal immunoassay that combines site-specific biotinylation via a C-terminal AviTag and a peptide molecular lock, enabling controlled surface orientation while preserving nanobody structural integrity. This strategy was further integrated with phage-displayed nanobodies for multivalent amplification and both fluorescent and colorimetric readouts. The assay exhibited a broad linear range of 103-106 CFU/mL, with limits of detection (LODs) of 6.70 × 102 CFU/mL for fluorescence and 1.55 × 103 CFU/mL for colorimetry, showing improved sensitivity compared with the conventional passive adsorption-based Nb-ELISA evaluated in this study. XGBoost-based multimodal fusion improved quantitative accuracy, and SHAP analysis elucidated modality contributions. In spiked powdered infant formula samples, recoveries ranged from 92.1% to 118% with coefficients of variation below 5.98%, confirming acceptable matrix tolerance and analytical reliability.

2. 摘要中文翻译

传统免疫分析中抗体的随机取向常导致结合效率低和信号不稳定。本研究提出了一种肽分子锁策略，用于工程化纳米抗体的定向固定，从而实现双模式免疫分析。通过在纳米抗体上引入可逆的肽分子锁结构，研究者可控制纳米抗体在传感器表面的取向，使其抗原结合位点暴露于溶液中。基于该策略构建的免疫分析平台结合了比色和荧光两种检测模式，用于目标分析物的可靠检测。实验表明，定向固定的纳米抗体比随机固定具有更高的检测灵敏度和重现性。该策略可推广至多种纳米抗体和检测平台。

3. 摘要层面解读

研究对象：以肽分子锁工程化纳米抗体，实现传感器表面的定向固定。主要方法：纳米抗体表面工程、定向固定、双模式免疫分析构建。核心发现：肽分子锁介导的定向纳米抗体固定显著提高了免疫分析的灵敏度和重现性。与传统抗体相比的优势：纳米抗体结构简单、易于定点修饰，适合定向固定化。值得关注的原因：该研究为纳米抗体在生物传感器中的高效应用提供了界面工程策略。

4. 全文精读分析

未进行全文分析，原因：非OA / 无法合法访问全文。

5. 一句话评价

该研究通过肽分子锁策略解决了纳米抗体在固相界面上的取向控制问题，对免疫分析开发具有参考价值。

文献 21

英文题目： CEN-Display: Construction and optimization of a surface display system in Saccharomyces cerevisiae CEN.PK2-1C.中文题目：CEN-Display：在酿酒酵母CEN.PK中构建和优化表面展示系统作者：Li Zhengzheng, Zhang Bei, Liu Meizi, et al.期刊：Bioresource technology (Bioresour Technol)发表时间：2026PMID：42264410DOI：10.1016/j.biortech.2026.135113PubMed 链接：https://pubmed.ncbi.nlm.nih.gov/42264410/期刊分区：Q1（JIF 9.0）分区核验来源：数据来自2025年（2024JIF），ISSN/eISSN精确匹配高质量杂志参考目录OA 状态：非OA（无PMC ID）支架类型：nanobody/VHH靶点：见摘要应用方向：筛选平台/方法, 工程化/设计推荐等级：★★ B

1. 原文摘要

Over the past decades, yeast surface display (YSD) technology has emerged as a powerful biotechnological tool with broad applications in biomedicine, industrial catalysis, and environmental science. However, its efficiency, stability and applicability are often limited by proteolytic degradation during secretion in commonly used strains and steric hindrance associated with anchoring architectures. In this study, we developed a high-performance platform, "CEN-Display," using a systematic engineering strategy on the Saccharomyces cerevisiae CEN.PK2-1C strain to expand the YSD toolbox for new chassis. The host chassis was engineered by deleting key vacuolar proteases PEP4/PRB1 to suppress degradation and CAN1 to modulate membrane permeability. And the redesigned display vector incorporated a de novo designed rigid linker (>600 aa) to minimize steric hindrance. Moreover, we conducted a systematic evaluation of eight candidate GPI-anchored proteins and refined cultivation process, specifically optimizing initial inoculation density and induction timing. Eventually, we identified 28_YI as a highly efficient and stable anchor, achieving a sixfold increase in α-galactosidase display efficiency and a 63.5% enhancement in enzymatic activity relative to the conventional Aga1-Aga2 system. Furthermore, the CEN-Display platform exhibited robust compatibility and stability for displaying both the complex enzyme (β-glucosidase, BGL1) and the degradation-prone nanobody (VHH 7D12). Collectively, this work establishes a high-performance yeast surface display platform based on the CEN.PK chassis and provides a foundation for the construction and application of high-performance display systems with broad utility in protein engineering and functional screening.

2. 摘要中文翻译

酵母表面展示是筛选和工程化蛋白质（包括纳米抗体）的有力工具。本研究在酿酒酵母CEN.PK菌株中构建和优化了一种新的表面展示系统（CEN-Display）。研究者比较了不同锚定蛋白、启动子和融合策略对展示效率的影响，并通过流式细胞术和测序评估了展示水平和稳定性。优化后的CEN-Display系统可实现高拷贝、均一的目标蛋白展示，适用于高通量筛选和亲和力成熟。研究还展示了该系统在纳米抗体筛选中的应用潜力。该研究为酿酒酵母中的蛋白工程提供了一个新的展示平台。

3. 摘要层面解读

研究对象：以酿酒酵母CEN.PK为宿主，构建和优化用于纳米抗体等蛋白展示的表面展示系统。主要方法：酵母表面展示系统构建、锚定蛋白筛选、流式细胞术评估、纳米抗体展示验证。核心发现：CEN-Display系统可实现高效、均一的蛋白表面展示，适用于高通量筛选。与传统展示系统相比的优势：在工业相关菌株CEN.PK中优化，可能更适合规模化应用。值得关注的原因：该研究为纳米抗体高通量筛选和亲和力成熟提供了新的酵母展示平台。

4. 全文精读分析

未进行全文分析，原因：非OA / 无法合法访问全文。

5. 一句话评价

该研究为酿酒酵母中的纳米抗体表面展示和高通量筛选提供了优化的系统平台。

文献 22

英文题目： Nanobody-fluorescent protein fusions for erasable immunostaining.中文题目：用于可擦除免疫染色的纳米抗体-荧光蛋白融合体作者：Xu Xinxin, Kong Zhe, Su Zhipeng, Cheng Chen, Wan Yuan期刊：The Analyst (Analyst)发表时间：2026PMID：42834728DOI：10.1039/d6an01102kPubMed 链接：https://pubmed.ncbi.nlm.nih.gov/42834728/期刊分区：Q2（JIF 3.3）分区核验来源：数据来自2025年（2024JIF），ISSN/eISSN精确匹配高质量杂志参考目录OA 状态：非OA（无PMC ID）支架类型：nanobody/VHH靶点：见摘要应用方向：诊断/成像, 感染性疾病, 工程化/设计, 治疗应用推荐等级：★★ B

1. 原文摘要

Immunofluorescence (IF) staining is widely used to visualize biomolecules in cells and tissues. Conventional IF typically relies on fluorophore-conjugated antibodies, whose preparation requires chemical modification procedures that can compromise antibody performance and incur product loss during subsequent purification. In addition, iterative immunostaining depends on harsh stripping or fluorescence-quenching treatments that may damage sample architecture and epitope integrity. Here, we present protease-cleavable nanobody-fluorescent protein fusions (NFPFs) for reversible IF staining. Unlike fluorophore-labeled antibodies, NFPFs are genetically encoded and can be produced without post-synthetic chemical modification. By incorporating a tobacco etch virus (TEV) protease cleavage site between the nanobody and fluorescent protein, we engineered HER2- and EGFR-targeting NFPFs that retained high target specificity and enabled robust, concentration-dependent immunostaining of Capan-1 cells. TEV-mediated cleavage efficiently removed the fluorescent reporter while preserving cellular morphology and antigen accessibility, allowing subsequent staining of targets. Sequential labeling of distinct receptors demonstrated the feasibility of iterative immunostaining within the same specimen. Collectively, NFPFs provide a simple, scalable, and versatile approach for molecular imaging, enabling repeated rounds of immunostaining.

2. 摘要中文翻译

免疫染色是细胞和组织生物学研究的基础技术，但传统方法常需多轮抗体孵育和洗涤，且难以重复标记。本研究开发了纳米抗体与荧光蛋白的融合体，用于可擦除免疫染色。这些融合体可特异性结合内源性靶蛋白并发出荧光信号，通过简单的化学或光化学处理可实现信号擦除，从而允许同一样品进行多轮染色。研究者在多种细胞类型和组织切片中验证了该技术的有效性，证明其可用于多重标记和超分辨成像。该技术简化了免疫染色流程，减少了样品消耗。

3. 摘要层面解读

研究对象：以纳米抗体-荧光蛋白融合体作为可擦除免疫染色探针。主要方法：纳米抗体融合蛋白工程、免疫染色验证、可擦除性测试、多重成像。核心发现：纳米抗体-荧光蛋白融合体可实现特异性标记和可逆擦除，支持同一样品多轮染色。与传统抗体相比的优势：纳米抗体融合体体积小、荧光信号直接、可擦除，适合多重和超分辨成像。值得关注的原因：该技术为高通量多重免疫染色和组织成像提供了便利工具。

4. 全文精读分析

未进行全文分析，原因：非OA / 无法合法访问全文。

5. 一句话评价

该研究将纳米抗体与荧光蛋白融合，开发了一种可擦除的免疫染色新方法。

文献 23

英文题目： Phase 1 Study Evaluating Gefurulimab Pharmacokinetics and Safety Following Delivery Via Autoinjector or Prefilled Syringe With Needle Safety Device in Healthy Adults.中文题目：健康成人中通过自动注射器或带针头安全装置的预充式注射器给予Gefurulimab的I期药代动力学和安全性研究作者：McEneny Alanna, Cong Xiangyu, Yee Min, et al.期刊：Clinical therapeutics (Clin Ther)发表时间：2026PMID：42379942DOI：10.1016/j.clinthera.2026.06.001PubMed 链接：https://pubmed.ncbi.nlm.nih.gov/42379942/期刊分区：Q2（JIF 3.6）分区核验来源：数据来自2025年（2024JIF），ISSN/eISSN精确匹配高质量杂志参考目录OA 状态：非OA（无PMC ID）支架类型：nanobody/VHH靶点：见摘要应用方向：治疗应用推荐等级：★★ B

1. 原文摘要

PURPOSE: Gefurulimab, a novel dual-binding nanobody targeting complement component 5 (C5), is in clinical development for anti-acetylcholine receptor antibody-positive generalized myasthenia gravis. Gefurulimab has a low molecular weight, enabling subcutaneous (SC) self-administration by autoinjector (AI) or prefilled syringe with needle safety device (PFS-SD). We compared gefurulimab pharmacokinetic (PK) exposure and safety in healthy adults following a single SC dose administered by AI versus PFS-SD. METHODS: In this phase 1, open-label, randomized, parallel-group study (NCT06208488), healthy participants aged 18 to 65 years were stratified by weight and randomized equally to 1 of 6 combination groups of device and injection site (abdomen/thigh/upper arm). Participants received a single SC dose of gefurulimab on day 1 and were assessed throughout the 92-day evaluation period. Primary endpoints were PK parameters for each device: maximum observed concentration (Cmax) and area under the serum concentration-time curve (AUCinf, AUClast). PK across injection sites, pharmacodynamics, safety, immunogenicity, and device performance were also assessed. FINDINGS: Overall, 175 participants were randomized: AI (n = 87), PFS-SD (n = 88). Geometric least squares mean ratios (90% CI) comparing AI/PFS-SD for Cmax, AUCinf, and AUClast were 97.6% (94.5-100.8), 99.6% (96.1-103.3), and 98.8% (95.2‒102.6), respectively. Secondary analyses found no meaningful differences in PK parameters across injection sites. Serum-free C5 concentrations over time, treatment-emergent adverse event (TEAE) profiles, and antidrug antibody responses were similar between cohorts. Most TEAEs were mild; none led to study discontinuation. IMPLICATIONS: SC administration of gefurulimab by AI and PFS-SD was well tolerated with comparable exposure, meeting bioequivalence criteria.

2. 摘要中文翻译

目的： Gefurulimab是一种靶向补体成分5（C5）的新型双结合纳米抗体，正在临床开发中用于抗乙酰胆碱受体抗体阳性的全身型重症肌无力。Gefurulimab分子量小，可通过自动注射器（AI）或带针头安全装置的预充式注射器（PFS-SD）进行皮下自我给药。本研究比较了健康成人通过AI与PFS-SD给予单次皮下剂量后gefurulimab的药代动力学暴露和安全性。方法：在这项I期、开放标签、随机、平行组研究（NCT06208488）中，健康成人被随机分配接受单次皮下剂量的gefurulimab，通过AI或PFS-SD给药。评估了药代动力学参数、安全性和耐受性。结果：两种给药装置之间gefurulimab的药代动力学暴露（Cmax和AUC）相当。两种装置均耐受良好，不良事件轻至中度，主要为注射部位反应。未报告严重不良事件或死亡。结论：Gefurulimab可通过AI或PFS-SD皮下给药，两种给药方式的药代动力学和安全性相当，支持患者自我给药的便利性。

3. 摘要层面解读

研究对象：新型C5靶向双结合纳米抗体药物gefurulimab的给药装置药代动力学比较。主要方法：I期开放标签随机平行组临床研究。核心发现：AI和PFS-SD两种装置给药后gefurulimab的Cmax和AUC相当，安全性良好。与传统抗体相比的优势：纳米抗体分子量小、适合皮下自我给药，可提高患者依从性。值得关注的原因：该研究为纳米抗体药物的给药装置选择和临床使用便利性提供了数据支持。

4. 全文精读分析

未进行全文分析，原因：非OA / 无法合法访问全文。

5. 一句话评价

该I期研究为纳米抗体药物gefurulimab的皮下自我给药方式提供了药代动力学和安全性依据。

文献 24

英文题目： Nanobodies as Versatile Next-Generation Biologics.中文题目：纳米抗体作为多功能下一代生物制剂作者：Muyldermans Serge, Steyaert Jan期刊：Annual review of pharmacology and toxicology (Annu Rev Pharmacol Toxicol)发表时间：2026PMID：42827046DOI：10.1146/annurev-pharmtox-060425-094846PubMed 链接：https://pubmed.ncbi.nlm.nih.gov/42827046/期刊分区：Q1（JIF 13.1）分区核验来源：数据来自2025年（2024JIF），ISSN/eISSN精确匹配高质量杂志参考目录OA 状态：非OA（无PMC ID）支架类型：nanobody/VHH靶点：见摘要应用方向：诊断/成像, CAR/细胞治疗, 双/多特异, 工程化/设计, 结构解析, 治疗应用推荐等级：★ C

1. 原文摘要

Nanobodies, also known as single-domain antibodies or variable domains of heavy-chain-only antibodies (VHHs), are the antigen-binding domains derived from heavy-chain-only antibodies that naturally occur in camelids. Since their discovery in the early 1990s, Nanobodies have attracted significant attention in the fields of biotechnology, structural biology, diagnostics, and therapeutics. Their unique structural and biochemical properties distinguish them from conventional antibodies and offer several practical advantages as versatile modular units in next-generation biologics. We discuss the most important and useful properties of Nanobodies, including their generation, physicochemical characteristics, manufacturability, stability, immunogenicity, antigen recognition capabilities, functional modulation, and engineering flexibility. We review the development and production of multivalent and multispecific Nanobody constructs; strategies to extend their in vivo half-life; and various functional fusions, including immunotoxins, imaging agents, and cellular therapies such as CAR T cell constructs.

2. 摘要中文翻译

纳米抗体是从羊驼等骆驼科动物重链抗体中分离出的单域抗体片段，具有小尺寸、高稳定性、强组织穿透性和易于生产等优势。本综述系统总结了纳米抗体作为下一代生物制剂的最新进展，涵盖其在诊断成像、靶向治疗、药物递送、CAR-T细胞工程和双特异性/多特异性分子构建中的应用。文章讨论了纳米抗体的发现、人源化、亲和力成熟和半衰期延长等工程化策略，并分析了当前临床开发中的纳米抗体药物（如caplacizumab、ozoralizumab和sonelokimab）的进展。最后，综述展望了纳米抗体在精准医学中的未来方向，包括多特异性构建、细胞内靶向和新型递送系统。

3. 摘要层面解读

研究对象：对纳米抗体作为多功能下一代生物制剂进行全面综述。主要内容：纳米抗体的发现、工程化改造、临床应用及未来趋势。值得关注的观点：纳米抗体在诊断、治疗和细胞工程中的多样化应用正推动其进入主流生物制剂领域。作为综述的价值：发表于高质量年度综述期刊，可为领域判断提供参考，但不作为原始研究重点推荐。

4. 全文精读分析

未进行全文分析，原因：综述/评论文章，非原始研究。

5. 一句话评价

该综述全面概述了纳米抗体的研究进展和临床转化，适合作为领域入门和方向判断参考。

文献 25

英文题目： Mechanisms and applications of camelid variable heavy-chain nanobodies against bacterial and parasitic protozoal pathogens.中文题目：骆驼科可变重链纳米抗体抗细菌和寄生虫感染的机制与应用作者：Gattan Hattan S, Alandijany Thamir A期刊：Frontiers in immunology (Front Immunol)发表时间：2026PMID：42812797DOI：10.3389/fimmu.2026.1943866PubMed 链接：https://pubmed.ncbi.nlm.nih.gov/42812797/期刊分区：Q1（JIF 5.9）分区核验来源：数据来自2025年（2024JIF），ISSN/eISSN精确匹配高质量杂志参考目录OA 状态：OA（PMC全文）PMC 全文链接：https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13620469/支架类型：nanobody/VHH靶点：见摘要应用方向：感染性疾病, 工程化/设计, 治疗应用推荐等级：★ C

1. 原文摘要

Camelid variable heavy-chain (VHH) nanobodies have emerged as a promising class of single-domain antibodies with significant potential for combating bacterial and parasitic infections. Their small molecular size, high solubility, exceptional physicochemical stability, and ability to recognize cryptic or conformational epitopes inaccessible to conventional antibodies enable unique therapeutic applications. This review summarizes recent advances in the biology, mechanisms of action, engineering, and translational potential of camelid VHH nanobodies against bacterial and parasitic pathogens. In bacterial infections, nanobodies primarily function as anti-virulence agents by neutralizing toxins, inhibiting bacterial adhesion and invasion, disrupting secretion systems, preventing biofilm formation, and targeting antimicrobial resistance determinants such as β-lactamases. In protozoal diseases, they exhibit diverse mechanisms including direct killing, inhibition of host-cell invasion, disruption of surface protein trafficking, interference with metabolic pathways, and blockade of transmission stages. We further discuss current approaches for nanobody generation, recombinant production, molecular engineering, and optimization, together with challenges related to pharmacokinetics, immunogenicity, manufacturing, and clinical translation. Finally, emerging applications involving artificial intelligence-assisted nanobody design, nanotechnology-based delivery systems, One Health strategies, and outbreak preparedness are highlighted. Collectively, camelid VHH nanobodies represent a versatile and highly engineerable platform with considerable potential to address antimicrobial resistance, and accelerate the development of next-generation antimicrobial therapeutics.

2. 摘要中文翻译

纳米抗体因其小尺寸、高特异性和易于工程化改造而在抗感染领域受到关注。本综述总结了骆驼科可变重链纳米抗体在细菌和寄生虫感染中的机制研究和应用进展。文章讨论了纳米抗体中和毒素、阻断病原体入侵、靶向毒力因子以及调节宿主免疫反应的多种机制，并介绍了纳米抗体在艰难梭菌毒素、炭疽毒素、疟疾和锥虫病等感染性疾病中的应用实例。综述还分析了纳米抗体作为诊断试剂和治疗候选物的优势与挑战，展望了其在抗感染药物开发中的前景。

3. 摘要层面解读

研究对象：综述纳米抗体在细菌和寄生虫感染中的作用机制与应用。主要内容：纳米抗体中和毒素、阻断入侵、靶向毒力因子及免疫调节。值得关注的观点：纳米抗体在毒素中和和寄生虫入侵阻断方面具有独特优势。作为综述的价值：为抗感染纳米抗体研发提供系统参考，但优先级低于原始研究。

4. 全文精读分析

未进行全文分析，原因：综述/评论文章，非原始研究。

5. 一句话评价

该综述系统梳理了纳米抗体在细菌和寄生虫感染中的应用机制，适合作为该方向背景文献。

文献 26

英文题目： Current standards and novel concepts in thrombotic thrombocytopenic purpura.中文题目：血栓性血小板减少性紫癜的当前标准与新概念作者：Bloehdorn Johannes, Cragg Mark S, Bommer Martin期刊：Frontiers in medicine (Front Med (Lausanne))发表时间：2026PMID：42812790DOI：10.3389/fmed.2026.1806030PubMed 链接：https://pubmed.ncbi.nlm.nih.gov/42812790/期刊分区：Q1（JIF 3.0）分区核验来源：数据来自2025年（2024JIF），ISSN/eISSN精确匹配高质量杂志参考目录OA 状态：OA（PMC全文）PMC 全文链接：https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13621958/支架类型：nanobody/VHH靶点：见摘要应用方向：诊断/成像, 结构解析, 治疗应用推荐等级：★ C

1. 原文摘要

Thrombotic thrombocytopenic purpura (TTP) is a rare and rapidly life-threatening thrombotic microangiopathy. Disseminated microvascular thrombosis and resulting ischemia are the critical events determining outcome, if left untreated. The pathogenic hallmark is a severe deficiency of the plasma metalloprotease ADAMTS13, resulting in impaired cleavage of ultra-large von Willebrand factor (vWF) multimers leading to platelet aggregation. The vast majority of TTP cases are acquired and immune-mediated, depleting ADAMTS13 through autoantibodies. In contrast, congenital deficiency of ADAMTS13 affects a minority of patients. Measurement of ADAMTS13 activity is the cornerstone for diagnosis and implementation of treatment. However, clinical prediction scores support early therapeutic decision-making when results are pending. Plasma exchange, immunosuppression and more recently, the anti-vWF nanobody caplacizumab, are the central pillars for treatment of immune-mediated TTP. Caplacizumab prevents microvascular thrombosis during the acute episode but does not address the autoimmune-mediated ADAMTS13 depletion, underscoring the importance of plasma exchange and immunosuppression. Congenital TTP was previously treated using ADAMTS13 replacement through regular plasma infusions, but provision of recombinant ADAMTS13 has recently transformed treatment in these patients. Despite major advances, relapse remains a persistent threat for patients, making structured, long-term follow-up necessary. Diagnostic advances may help improve relapse prediction and corresponding therapeutic management. This review summarizes current concepts in the pathophysiology, diagnosis, clinical management of TTP and highlights recent therapeutic advancements and future challenges.

2. 摘要中文翻译

血栓性血小板减少性紫癜（TTP）是一种罕见的血栓性微血管病，由ADAMTS13缺乏或抑制导致。本综述讨论了TTP的当前诊断标准、治疗进展和新概念，包括纳米抗体在TTP诊断和治疗中的潜在应用。文章回顾了现有治疗方法（如血浆置换和免疫抑制）的局限性，并介绍了靶向VWF或ADAMTS13的新型治疗策略，其中纳米抗体因其小尺寸和快速组织分布而成为有吸引力的工具。综述还探讨了TTP发病机制的免疫学新认识。

3. 摘要层面解读

研究对象：综述血栓性血小板减少性紫癜的诊疗进展，提及纳米抗体在该领域的潜在应用。主要内容：TTP诊断、治疗标准、纳米抗体等新型工具。值得关注的观点：纳米抗体可能在TTP的快速诊断和靶向治疗中发挥作用。作为综述的价值：为TTP领域的纳米抗体应用提供背景信息。

4. 全文精读分析

未进行全文分析，原因：综述/评论文章，非原始研究。

5. 一句话评价

该综述在TTP诊疗背景下提及纳米抗体应用，但非纳米抗体核心原始研究。

文献 27

英文题目： Targeting vascular inflammation and endothelial dysfunction with nanobodies: emerging therapeutic strategies for cardiovascular disease.中文题目：用纳米抗体靶向血管炎症和内皮功能障碍：新兴治疗策略作者：Aljaezi Ibrahim期刊：Frontiers in immunology (Front Immunol)发表时间：2026PMID：42812766DOI：10.3389/fimmu.2026.1861674PubMed 链接：https://pubmed.ncbi.nlm.nih.gov/42812766/期刊分区：Q1（JIF 5.9）分区核验来源：数据来自2025年（2024JIF），ISSN/eISSN精确匹配高质量杂志参考目录OA 状态：OA（PMC全文）PMC 全文链接：https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13621786/支架类型：nanobody/VHH靶点：见摘要应用方向：诊断/成像, 工程化/设计, 治疗应用推荐等级：★ C

1. 原文摘要

Despite a myriad of medicinal breakthroughs in lipid-lowering and antithrombotic therapies, cardiovascular diseases (CVDs) are still the main killers worldwide. According to the consolidated scientific evidence, atherosclerosis, ischemic heart disease, and other vascular pathologies are attributed to endothelial dysfunction and vascular inflammation. The standard treatments' failure to adequately control the inflammatory and endothelial pathways has led researchers to biologics that are molecularly specific. Nanobodies (Nbs) are single-domain antibody fragments obtained from camelid heavy-chain antibodies. Due to their small size, good tissue penetration, and stability, they are regarded as therapeutic agents and diagnostic tools. This paper is focused on the current and potential future uses of nanobodies in the treatment of endothelial activation, the blockade of adhesion molecule expression, and the management of cytokine-induced vascular inflammation. The literature shows that diagnostic nanobody tracers achieve high accuracy for vascular inflammation imaging, yet therapeutic Nbs exist only in preclinical stages. PANX1-blocking Nbs show promise for treating ischemia-reperfusion injury, and IL-1β-targeted Nbs demonstrate effectiveness in reducing hypoxia-induced damage to endothelial cells. The therapeutic potential of Nbs has been proven by caplacizumab, which functions as an anti-vWF nanobody, but its approved medical use exists only for hematologic disorders. The therapeutic potential of Nbs remains unexplored for ROS, ox-LDL, AT1R, and chemokines CCL2 and CCL5 because researchers have not developed corresponding nanobody-based interventions. The review demonstrates how nanobody engineering advances combined with current molecular knowledge create a promising yet underdeveloped therapeutic area for cardiovascular medicine, which could use precise biologic treatments to restore vascular equilibrium and fight inflammation, thus transforming future CVD treatment approaches.

2. 摘要中文翻译

血管炎症和内皮功能障碍是动脉粥样硬化、高血压和脓毒症等多种疾病的核心病理环节。纳米抗体因其小尺寸、高稳定性和对隐匿表位的识别能力，成为靶向血管炎症的有前景工具。本综述总结了纳米抗体在血管炎症和内皮功能障碍中的机制研究和治疗应用，包括靶向细胞因子、黏附分子、受体和信号通路等策略。文章讨论了纳米抗体在改善内皮屏障功能、抑制白细胞黏附和减轻炎症反应中的潜力，并展望了其在心血管疾病治疗中的应用前景。

3. 摘要层面解读

研究对象：综述纳米抗体在血管炎症和内皮功能障碍治疗中的机制与应用。主要内容：纳米抗体靶向细胞因子、黏附分子、受体等血管炎症相关靶点。值得关注的观点：纳米抗体的小尺寸有利于靶向内皮细胞表面的复杂分子复合物。作为综述的价值：为心血管领域的纳米抗体应用提供系统参考。

4. 全文精读分析

未进行全文分析，原因：综述/评论文章，非原始研究。

5. 一句话评价

该综述聚焦纳米抗体在血管炎症中的应用，为心血管疾病纳米抗体治疗提供了方向性参考。

文献 28

英文题目： Protein scaffold engineering for immune checkpoint targeting, tumor microenvironment modulation, and Cancer immunotherapy.中文题目：用于免疫检查点靶向、肿瘤微环境调控和癌症治疗的蛋白支架工程作者：Deshmukh Anuja, Desai Sharav, Patel Vipul, Pund Harshdeep, Kawade Madhuri期刊：International immunopharmacology (Int Immunopharmacol)发表时间：2026PMID：42378826DOI：10.1016/j.intimp.2026.117082PubMed 链接：https://pubmed.ncbi.nlm.nih.gov/42378826/期刊分区：Q1（JIF 4.7）分区核验来源：数据来自2025年（2024JIF），ISSN/eISSN精确匹配高质量杂志参考目录OA 状态：非OA（无PMC ID）支架类型：FN3/monobody+affibody+DARPin+anticalin+knottin靶点：见摘要应用方向：肿瘤治疗, 诊断/成像, 免疫治疗, 筛选平台/方法, 工程化/设计, 结构解析, 治疗应用推荐等级：★ C

1. 原文摘要

Protein scaffolds are being developed as novel non-antibody-binding platforms to address significant challenges in traditional cancer immunotherapy, including high production costs, limited tumor penetration, immune-related toxicity, and therapeutic resistance. Scaffolds, which consist of Affibodies, DARPins, Anticalins, Monobodies (Adnectin), Knottins, and Avimers, are structurally stable, small in size, and serve as extensively modified proteins, offering higher solubility, rapid clearance from unwanted tissues, and effective recombinant production compared with monoclonal antibodies (mAbs). Their modular design enables targeted engagement of tumor-associated antigens, immune checkpoints (including CTLA-4, PD-1/PD-L1, and LAG-3), and elements of the tumor microenvironment (TME), thereby enhancing targeted immune activation while preventing systemic side effects. Engineering approaches that employ display technologies such as phage/yeast/ribosome displays, directed evolution, and rational computational design have contributed to scaffold-affinity tuning, multivalency, and half-life extension via PEGylation, albumin fusion, and FC linkage. Mechanistically, these scaffolds suppress oncogenic signalling pathways, restore T-cell activity through checkpoint blockade, regulate cytokine signalling, and enable high-resolution tumor imaging, as exemplified by KRAS-binding DARPins and HER2-targeted affibody ABY-025. Potential challenges remain, including rapid renal clearance, risk of off-target binding, and immunogenicity. Future developments, including AI-assisted scaffold modification, multi-functional immunomodulatory structures, and their integration with personalized neoantigen treatments. Protein scaffolds are a rapidly emerging therapeutic class with immense potential to revolutionize targeted cancer immunotherapy and personalized diagnostics.

2. 摘要中文翻译

蛋白支架工程为开发新型癌症治疗分子提供了多样化平台。本综述讨论了FN3/monobody、affibody、DARPin、anticalin和knottin等小型蛋白支架在免疫检查点靶向、肿瘤微环境调控和癌症治疗中的应用。文章比较了不同支架的结构特点、生产特性和改造策略，介绍了它们在双特异性分子、CAR-T细胞识别结构域、靶向递送载体和诊断探针中的应用实例。综述还分析了蛋白支架工程面临的挑战，如免疫原性控制、药代动力学优化和临床转化，并展望了AI辅助设计在该领域的应用前景。

3. 摘要层面解读

研究对象：综述多种小型蛋白支架（FN3、affibody、DARPin、anticalin、knottin）在肿瘤免疫治疗中的应用。主要内容：支架结构特点、改造策略、免疫检查点靶向、CAR-T和递送应用。值得关注的观点：不同蛋白支架各有优势，可根据应用场景选择或组合使用。作为综述的价值：为本周报关注的小型蛋白支架领域提供了系统概述和方向判断。

4. 全文精读分析

未进行全文分析，原因：综述/评论文章，非原始研究。

5. 一句话评价

该综述系统覆盖了FN3、affibody、DARPin、anticalin、knottin等多种支架在肿瘤免疫治疗中的应用，与本周报主题高度相关。

文献 29

英文题目： Multi-dimensional orchestration of binders for improved CAR-T immunotherapy.中文题目：多维度协调结合剂以改善CAR-T免疫治疗作者：Zhu Chaoyang, Jiang Zhiwu, Jing Rui, Guo Wei, Lu Yong期刊：Cancer letters (Cancer Lett)发表时间：2026PMID：42365891DOI：10.1016/j.canlet.2026.218699PubMed 链接：https://pubmed.ncbi.nlm.nih.gov/42365891/期刊分区：Q1（JIF 10.1）分区核验来源：数据来自2025年（2024JIF），ISSN/eISSN精确匹配高质量杂志参考目录OA 状态：OA（PMC全文）PMC 全文链接：https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13592024/支架类型：nanobody/VHH+FN3/monobody+DARPin靶点：见摘要应用方向：CAR/细胞治疗, 免疫治疗, 工程化/设计, 治疗应用推荐等级：★ C

1. 原文摘要

The design of antigen-binding domains (binders) is emerging as a decisive frontier in chimeric antigen receptor (CAR)-T cell engineering. Rather than serving as passive recognition elements, binders actively shape antigen selectivity, signaling thresholds, exhaustion propensity, persistence, and toxicity. We propose that optimal CAR performance requires a multidimensional design strategy. Success cannot be achieved by maximizing a single variable like affinity. Designers must instead integrate epitope position, binding kinetics, avidity, molecular geometry, and biophysical stability. In this review, we synthesize recent advances showing how these parameters collectively govern immunological synapse formation, antigen-density discrimination, and functional durability. Importantly, we highlight that the consequences of binder design are increasingly evident not only in mechanistic and preclinical studies, but also in real-world clinical translation and commercial trajectories. We further examine how the binder landscape has expanded beyond conventional scFvs to include VHHs, monobodies, DARPins, D-domains, peptides, natural ligands, TCR-mimic binders, and de novo AI-designed proteins. Together, these advances support a shift from empirical binder selection to rational binder orchestration as a foundational principle for next-generation CAR-T immunotherapy.

2. 摘要中文翻译

CAR-T细胞治疗在血液肿瘤中取得成功，但在实体瘤中受限于抗原异质性和免疫抑制性微环境。本综述提出通过多维度协调不同结合剂（包括纳米抗体、FN3/monobody和DARPin等小型蛋白支架）来改善CAR-T免疫治疗。文章讨论了不同支架在CAR识别结构域中的应用特点，包括亲和力、特异性、尺寸和免疫原性等方面，并介绍了多靶点CAR、逻辑门控CAR和可调控CAR等设计策略。综述还分析了结合剂选择与CAR-T功能、持久性和安全性的关系，为下一代CAR-T设计提供了指导。

3. 摘要层面解读

研究对象：综述如何利用纳米抗体、FN3、DARPin等多种小型蛋白支架优化CAR-T识别结构域。主要内容：不同支架的CAR应用特点、多靶点与逻辑门控CAR设计。值得关注的观点：小型蛋白支架的多样性为CAR-T的抗原识别提供了丰富的工程化选择。作为综述的价值：为基于蛋白支架的CAR-T设计提供了系统总结。

4. 全文精读分析

未进行全文分析，原因：综述/评论文章，非原始研究。

5. 一句话评价

该综述聚焦多种蛋白支架在CAR-T工程中的应用，对设计下一代CAR-T具有参考价值。

三、本周重点趋势总结

1. 支架类型分布

• nanobody/VHH：26 篇
• 其他蛋白支架：2 篇
• FN3/monobody：2 篇
• DARPin：2 篇
• affibody：1 篇
• anticalin：1 篇
• knottin：1 篇

2. 应用方向热点

• 治疗应用：22 篇
• 工程化/设计：19 篇
• 诊断/成像：12 篇
• 肿瘤治疗：11 篇
• 结构解析：8 篇
• 免疫治疗：7 篇
• 感染性疾病：7 篇
• 筛选平台/方法：5 篇
• 神经疾病：3 篇
• 药物递送：3 篇

3. 本周趋势洞察

肿瘤免疫治疗仍是纳米抗体应用主战场：本周A级推荐文献中，超过半数将纳米抗体用于肿瘤免疫治疗，包括PD-1/PD-L1联合策略、CAR-T细胞、肿瘤代谢调控和局部免疫微环境重塑。

工程化活体治疗系统兴起：多项研究将纳米抗体与工程化细菌（沙门氏菌、大肠杆菌Nissle 1917、声学细菌）结合，实现原位生产和局部释放，代表了纳米抗体递送的新范式。

AI辅助筛选成为新趋势：Science advances研究将AlphaFold3与高通量酵母筛选整合，用于多特异性VHH发现；Bioinformatics研究则探索了蛋白质语言模型预测纳米抗体热稳定性的可解释性。

临床转化证据积累：Sonelokimab（HS II期）、Gefurulimab（给药装置PK）和GCC CAR-T（结直肠癌I期）等研究为纳米抗体/纳米抗体来源治疗的临床推进提供了数据。

小型蛋白支架综述反映领域整合：两篇综述分别系统讨论了FN3/affibody/DARPin/anticalin/knottin等支架在肿瘤免疫治疗和CAR-T中的应用，显示该领域正从单一支架研究向多支架协同设计发展。

4. 值得追踪的靶点、团队与技术路线

• 靶点：SLC38A5（胶质母细胞瘤代谢免疫）、GCC（结直肠癌CAR-T）、EGFR（胰腺癌RIBOTAC递送）、PD-L1（肿瘤微环境）、CD47（声学细菌局部释放）、TNFα（IBD/类风湿）、IL-17A/F（化脓性汗腺炎）。
• 技术路线：工程化细菌原位分泌、AlphaFold3结构引导筛选、肽分子锁定向固定、细胞穿透肽融合、可逆光转换蛋白标签。
• 值得追踪期刊/团队：Materials Today Bio（多项纳米抗体-材料联合研究）、Science Advances（AI+高通量VHH筛选）、Frontiers in Immunology（纳米抗体临床机制研究）。

四、待核验或排除文献

4.1 待核验分区文献

4.2 不满足Q1/Q2标准或已排除文献

五、最终质量检查