Science Advances最新文献_第10页

Targeting transthyretin by one Cas9 variant with superfidelity and broad compatibility 靶向转甲状腺素的Cas9变体具有超高保真度和广泛的兼容性

IF 12.5 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Advances

Pub Date : 2026-01-02 DOI: 10.1126/sciadv.adu6505

Sixian Qi, Lifan Wei, Zhan Ding, Feiya Zhong, Sicong Yang, Leibin Wu, Xuan Yang, Bin Kang, Mo Dan, Jianhua Gan, Chunlei Li, Xiaoye Su

Amyloid transthyretin (ATTR) amyloidosis is a fatal disease caused by the accumulation of misfolded transthyretin proteins. Although knocking down the TTR gene by CRISPR-Cas9 represents a promising strategy for treating ATTR amyloidosis, its efficiency and safety remain to be further investigated. Here, we report a systematic investigation of SpCas9-based TTR editing. Besides the target site, wild-type SpCas9 and the reported variants induced extensive off-target edits. To improve the fidelity, we performed structural analysis and designed a series of SpCas9 variants. Studies demonstrated that SpCas9-Mut5 is an ultrahigh-fidelity variant, which induces extremely low levels of off-target edits and translocations without substantial impairment of on-target editing activity. SpCas9-Mut5 is compatible with the adenine base editor (ABE) system, markedly reducing off-target edits and narrowing the editing window. In conclusion, our study suggests that SpCas9-Mut5 is an excellent candidate for TTR gene editing. Besides ATTR amyloidosis, SpCas9-Mut5 and its derivative ABE could be widely used in the treatment of other diseases.

淀粉样转甲状腺素（ATTR）淀粉样变性是由错误折叠的转甲状腺素蛋白积累引起的一种致命疾病。虽然CRISPR-Cas9敲除TTR基因是治疗ATTR淀粉样变性的一种很有前景的策略，但其有效性和安全性仍有待进一步研究。在这里，我们报告了基于spcas9的TTR编辑的系统调查。除了目标位点外，野生型SpCas9和报道的变体还诱导了广泛的脱靶编辑。为了提高保真度，我们进行了结构分析并设计了一系列SpCas9变体。研究表明，SpCas9-Mut5是一种超高保真度的变体，它诱导极低水平的脱靶编辑和易位，而不会严重损害靶编辑活性。SpCas9-Mut5与腺嘌呤碱基编辑器（ABE）系统兼容，显著减少脱靶编辑并缩小编辑窗口。综上所述，我们的研究表明SpCas9-Mut5是TTR基因编辑的优秀候选者。除ATTR淀粉样变性外，SpCas9-Mut5及其衍生物ABE可广泛应用于其他疾病的治疗。

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引用次数: 0

Spaceflight alters molecular networks linked to diverse human diseases in a single cellular model 太空飞行改变了单个细胞模型中与多种人类疾病相关的分子网络

IF 12.5 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Advances

Pub Date : 2026-01-02 DOI: 10.1126/sciadv.adw7832

Wijdan Al-Ahmadi, Rayyanah Barnawi, Edward G. Hitti, Khalid S. A. Khabar

The International Space Station provides an opportunity to study the impact of spaceflight on gene expression and possible links to human health. Our study investigates global changes in messenger RNA (mRNA) abundance in the THP-1 cell line, a monocyte-macrophage lineage known for plasticity and immune reprogramming features. We identified pathways positively enriched with genes affecting muscle and cardiac contraction, neuronal system, and sensory perception. Available computational models identified links with health issues, including cardiac, neurological, muscular, and renal disorders and alterations in senses. Specific mechanistic networks were identified: retinoid metabolism, cAMP (adenosine 3′,5′-monophosphate)/CREB (cAMP response element–binding protein) signaling, and glutamatergic receptor signaling, which were associated with changes in vision, sleep, and movement, respectively. A considerable reduction is observed in E2F-regulated transcription of G₂-M and DNA repair genes. A c-myc–regulated mRNA splicing pathway was identified and found commonly down-regulated in other mission datasets. Our results offer a stimulating framework for several health states encountered during spaceflight and can be further used as an accelerated disease and drug discovery model.

国际空间站为研究航天飞行对基因表达的影响及其与人类健康的可能联系提供了机会。我们的研究调查了THP-1细胞系中信使RNA （mRNA）丰度的全球变化，THP-1细胞系是一种单核巨噬细胞谱系，以可塑性和免疫重编程特征而闻名。我们确定了富含影响肌肉和心脏收缩、神经系统和感觉知觉的基因的途径。现有的计算模型确定了与健康问题的联系，包括心脏、神经、肌肉和肾脏疾病以及感官改变。确定了特定的机制网络：类维生素a代谢、cAMP（腺苷3′，5′-单磷酸腺苷）/CREB （cAMP反应元件结合蛋白）信号传导和谷氨酸受体信号传导，它们分别与视力、睡眠和运动的变化有关。在e2f调节的G2-M和DNA修复基因的转录中观察到相当大的减少。c-myc调控的mRNA剪接途径在其他任务数据集中普遍下调。我们的研究结果为在太空飞行中遇到的几种健康状态提供了一个刺激的框架，可以进一步用作加速疾病和药物发现模型。

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引用次数: 0

Tunneling field emission from nano-optics under electron irradiation 电子辐照下纳米光学的隧穿场发射

IF 12.5 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Advances

Pub Date : 2026-01-02 DOI: 10.1126/sciadv.ady5421

Kenan Elibol, Vesna Srot, Chao Yang, Sayooj Satheesh, Serkan Arslan, Marko Burghard, Harald Giessen, Peter A. van Aken

While field emission, which is crucial for sub–angstrom resolution imaging and nanofabrication, has been extensively investigated in high-voltage and laser-driven systems, its realization through plasmonics under electron irradiation remains unexplored. Here, we demonstrate a proof of concept for electron beam–driven field emission from plasmonic emitter arrays with nanoscale hotspots acting as highly efficient emission sites, which also exhibit strong surface-enhanced Raman scattering activity. The electron beam–induced field distributions and electrical polarization switching are visualized by four-dimensional scanning transmission electron microscopy. Classical and quantum-corrected electromagnetic simulations combined with experimental field maps identify the highest field intensities at the apex of emitter tips. Optical excitation experiments confirm the giant field enhancement at these locations. In situ electrical measurements in a transmission electron microscope reveal a distinct tunneling field emission signature that surpasses secondary electron emission. The demonstrated field emission mechanism opens unexplored possibilities for realizing spatially confined electron sources with ultrafast temporal switching capabilities.

虽然场发射对于亚埃分辨率成像和纳米制造至关重要，已经在高压和激光驱动系统中得到了广泛的研究，但在电子辐照下通过等离子体实现场发射仍未得到探索。在这里，我们展示了等离子体发射器阵列的电子束驱动场发射的概念证明，纳米级热点作为高效发射位点，也表现出强烈的表面增强拉曼散射活性。利用四维扫描透射电镜观察了电子束诱导场分布和电极化开关。经典和量子校正的电磁模拟结合实验场图确定了发射极尖端的最高场强。光激发实验证实了这些位置的巨大场增强。在透射电子显微镜下的原位电测量揭示了一个明显的隧道场发射特征，超过了二次电子发射。所展示的场发射机制为实现具有超快时间开关能力的空间受限电子源开辟了尚未探索的可能性。

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引用次数: 0

Dynamic changes in phycosphere carbonate chemistry reveal rapid modulation of carbon uptake in single diatom cells 藻球碳酸盐化学的动态变化揭示了单个硅藻细胞碳吸收的快速调节

IF 12.5 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Advances

Pub Date : 2026-01-02 DOI: 10.1126/sciadv.ady8646

Matthew Keys, Andrea Highfield, Abdul Chrachri, Clare Ostle, Colin Brownlee, Glen L. Wheeler

Diatoms use multiple mechanisms of dissolved inorganic carbon (DIC) uptake to maintain CO₂ supply to RuBisCO (ribulose-1,5-bisphosphate carboxylase/oxygenase), but how these different pathways are coordinated in response to rapid changes in their environment remains unclear. By measuring the dynamic changes in phycosphere carbonate chemistry around single diatom cells, we show that DIC uptake is rapidly modulated. We find that external carbonic anhydrase (eCA) plays a major role in DIC uptake in large centric diatoms at ambient seawater CO₂, but there is a strong switch to direct HCO₃⁻ uptake under low CO₂. Inhibition of eCA leads to rapid activation of HCO₃⁻ uptake, which can compensate for the loss of eCA activity under lower irradiances. These different modes of DIC uptake have distinct influences on phycosphere carbonate chemistry that may directly affect nutrient acquisition and biotic interactions. Our findings reveal that dynamic modulation of DIC uptake allows diatoms to rapidly respond to changes in CO₂ supply and demand.

硅藻利用多种溶解无机碳（DIC）摄取机制来维持对RuBisCO（核酮糖-1,5-二磷酸羧化酶/加氧酶）的二氧化碳供应，但这些不同的途径如何协调以应对环境的快速变化尚不清楚。通过测量单个硅藻细胞周围藻球碳酸盐化学的动态变化，我们发现DIC的摄取是快速调节的。我们发现外部碳酸酐酶（eCA）在大中心硅藻在海水CO2环境下对DIC的吸收中起主要作用，但在低CO2环境下，直接对HCO3−的吸收发生了强烈的转变。抑制eCA导致HCO3−摄取的快速激活，这可以补偿低辐照下eCA活性的损失。这些不同的DIC吸收模式对藻球碳酸盐化学有不同的影响，可能直接影响营养获取和生物相互作用。我们的研究结果表明，DIC吸收的动态调节使硅藻能够快速响应二氧化碳供需的变化。

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引用次数: 0

Integrin inhibition facilitates fibrocartilaginous transformation in connective tissue in osteoarthritis 整合素抑制促进骨关节炎结缔组织中的纤维软骨转化

IF 12.5 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Advances

Pub Date : 2026-01-02 DOI: 10.1126/sciadv.ady4112

Ruiye Bi, Xianni Yang, Haohan Li, Yanjing Zhan, Qing Yin, Han Fang, Ziqian Wang, Binbin Ying, Haopeng Yu, Songsong Zhu

Osteoarthritis (OA) is a disabling condition with pathological remodeling of different joints, resulting in impaired function of the whole musculoskeletal system in vertebrates. Fibrocartilage has poor self-repair capacity after OA, leading to restricted treatment strategies and unsatisfying clinical efficacy. Recently, we constructed the spatiotemporal multiomic landscape of fibrocartilage and connective tissue in human temporomandibular joint (TMJ)–OA, observing that adjacent connective tissue could transform to fibrocartilage in TMJ-OA. We found that the COL5A1⁺ fibroblast population, derived from perivascular niche, contributes to fibrocartilaginous extracellular matrix (ECM) transformation. Multijoint analysis showed that integrin α_V/β₅ was universally activated in OA joints, which led to increased fibrocartilaginous transcription but disarranged ECM transformation in connective tissues. In OA mouse models and a TMJ-OA miniature pig model, inhibition of integrin α_V/β₅ activity using cilengitide facilitated the transcriptional reprogramming of Col5a1⁺ fibroblast and functional remodeling of the connective tissues. Our findings verified the effectiveness of cilengitide and provided a clinical route for fibrocartilage injury repair in OA.

骨关节炎（OA）是脊椎动物不同关节的病理性重塑导致整个肌肉骨骼系统功能受损的致残性疾病。骨性关节炎后纤维软骨的自我修复能力较差，导致治疗策略受限，临床疗效不理想。最近，我们构建了人颞下颌关节(TMJ) -OA中纤维软骨和结缔组织的时空多组景观，观察到TMJ-OA中相邻结缔组织可以向纤维软骨转化。我们发现来自血管周围生态位的COL5A1+成纤维细胞群有助于纤维软骨细胞外基质（ECM）的转化。多关节分析显示，整合素αV/β5在OA关节中普遍激活，导致纤维软骨转录增加，但结缔组织中ECM转化紊乱。在OA小鼠模型和TMJ-OA微型猪模型中，西伦吉肽抑制整合素αV/β5活性促进了Col5a1+成纤维细胞的转录重编程和结缔组织的功能重塑。我们的研究结果证实了西伦吉肽的有效性，并为骨性关节炎的纤维软骨损伤修复提供了一条临床途径。

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引用次数: 0

Synergistic intragenic epigenetic deregulation by IDH2 and SRSF2 mutations causes mis-splicing of key transcriptional regulators 由IDH2和SRSF2突变引起的协同基因内表观遗传失调导致关键转录调控因子的错误剪接

IF 12.5 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Advances

Pub Date : 2026-01-02 DOI: 10.1126/sciadv.adu8292

Aristeidis G. Telonis, Robert F. Stanley, Emmalee R. Adelman, Akihide Yoshimi, Adedamola A. Adele, Angelique Cruz, Daniel H. Wiseman, Omar Abdel-Wahab, Maria E. Figueroa

Genes affecting DNA methylation (DNAme) are frequently comutated with splicing factors in acute myeloid leukemia (AML) and associate with more aggressive phenotypes. To elucidate the underlying molecular mechanisms, we deeply profiled wild-type and IDH2^R140Q/SRSF2^P95 single- or double-mutant AMLs. We find a unique set of mis-spliced genes and differentially methylated CpGs in double mutants. Mis-spliced exons are enriched in CCNG splicing enhancers and in the corresponding DNAme changes. Using a machine learning model, we can accurately predict exon inclusion levels from proximal CpGs. These CpGs are more likely to overlap footprints of RNA binding and chromatin-modifying complexes but not transcription factors. We also report unique gene expression profiles associated with each genotype; however, the differentially expressed genes do not overlap with mis-spliced transcripts. Instead, the mis-spliced genes encode for proteins that interact with the complexes regulating these differentially expressed genes. Thus, aberrant DNAme and splicing lead to the mis-splicing of key regulatory complexes, resulting in the aberrant gene expression profiles characteristic of these AMLs.

在急性髓性白血病（AML）中，影响DNA甲基化（DNAme）的基因经常与剪接因子相关联，并与更具侵袭性的表型相关。为了阐明潜在的分子机制，我们深入分析了野生型和IDH2R140Q/SRSF2P95单或双突变AMLs。我们在双突变体中发现了一组独特的错误剪接基因和差异甲基化的CpGs。错误剪接的外显子在CCNG剪接增强子和相应的DNAme变化中丰富。使用机器学习模型，我们可以准确地预测近端CpGs的外显子包含水平。这些CpGs更有可能重叠RNA结合和染色质修饰复合物的足迹，而不是转录因子。我们还报告了与每种基因型相关的独特基因表达谱；然而，差异表达的基因不会与错误剪接的转录物重叠。相反，错误剪接的基因编码蛋白质，与调节这些差异表达基因的复合物相互作用。因此，异常的dna和剪接导致关键调控复合物的错误剪接，从而导致这些AMLs特征的基因表达谱异常。

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引用次数: 0

Sustainable thermal paper formulation using lignocellulosic biomass fractions 使用木质纤维素生物质馏分的可持续热敏纸配方

IF 12.5 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Advances

Pub Date : 2026-01-02 DOI: 10.1126/sciadv.adw9912

Tom Nelis, Manon Rolland, Claire L. Bourmaud, Etiënne L. M. Vermeirssen, Ghezae Tekleab, Harm-Anton Klok, Jeremy S. Luterbacher

Thermal paper presents widely recognized health hazards due to its formulations containing bisphenol A (BPA) and bisphenol S (BPS) as color developers with limited research on safer alternatives. Here, we introduce sustainable thermal paper formulations built with functionalized lignin polymers and lignin-derived esters, combined with a sensitizer derived from xylan. Light-colored lignin polymer was obtained via sequential aldehyde-assisted fractionation, which reduced chromophore concentration through multiple extraction cycles. Good performance was achieved with polymeric lignin (color density at 120°C ≈ 0.8 to 1.1) when combined with xylan-derived diformylxylose (DFX), each of which is produced directly by simple biomass fractionation. Coatings remained stable for over a year under ambient conditions. Last, lignin-based developers showed estrogenic activity that was two to three orders of magnitude lower than BPA and one to two orders of magnitude lower than BPS, while the DFX sensitizer showed no signs of estrogenic activity or toxicity to bacteria or algae.

由于热敏纸的配方中含有双酚A （BPA）和双酚S （BPS）作为显色剂，因此对健康的危害是公认的，但对更安全的替代品的研究有限。在这里，我们介绍可持续热敏纸配方构建木质素聚合物和木质素衍生酯，结合从木聚糖衍生的敏化剂。通过连续醛辅助分离得到浅色木质素聚合物，通过多次提取循环降低了发色团的浓度。聚合物木质素（120°C时色密度≈0.8 ~ 1.1）与木聚糖衍生二甲酰木糖（DFX）结合，均可通过简单的生物质分馏直接生产。涂层在环境条件下保持稳定超过一年。最后，基于木质素的促敏剂显示出的雌激素活性比BPA低2到3个数量级，比BPS低1到2个数量级，而DFX增敏剂没有显示出雌激素活性或对细菌或藻类毒性的迹象。

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引用次数: 0

Metaoptics merging computational optics and optical computing toward intelligent visual perception 元光学融合了计算光学和光学计算，面向智能视觉感知

IF 12.5 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Advances

Pub Date : 2026-01-02 DOI: 10.1126/sciadv.aea8941

Yueqiang Hu, Hanbin Chi, Huigao Duan

Visual perception systems are evolving toward multifunctionality, miniaturization, and real-time intelligence, necessitating coadvancements in optical hardware and computational software. Computational optics enhances optical encoding through algorithms but faces computational limits, while optical computing offers photonic parallelism yet struggles with hardware complexity. Metaoptics, using subwavelength nanostructures for multidimensional light-field control, resolves this tension by serving dual roles: as an efficient computational optics encoder offloading algorithmic burdens and as a nanoscale optical computing processor enabling ultrahigh-density parallelism. This synergy drives computational optical integration for next-generation optoelectronics. This review outlines computational optics and optical computing fundamentals, analyzes metaoptics’ advantages in multidimensional optical information encoding and processing, and details recent metaoptics-based advances and challenges in computational optics, optical computing, and their convergence. The conclusion provides a future roadmap, highlighting metaoptics-driven integration’s potential for chip-scale intelligent visual perception by bridging the hardware-software divide to enable miniaturized devices with real-time adaptability, massive parallelism, and energy efficiency.

视觉感知系统正朝着多功能、小型化和实时智能的方向发展，这需要光学硬件和计算软件的共同进步。计算光学通过算法增强光学编码，但面临计算限制，而光学计算提供光子并行性，但与硬件复杂性作斗争。元光学使用亚波长纳米结构进行多维光场控制，通过发挥双重作用解决了这种紧张关系：作为一个有效的计算光学编码器减轻算法负担，作为一个纳米级光学计算处理器实现超高密度并行。这种协同作用推动了下一代光电子器件的计算光学集成。本文概述了计算光学和光学计算的基本原理，分析了元光学在多维光学信息编码和处理方面的优势，详细介绍了基于元光学的计算光学、光学计算及其融合的最新进展和挑战。结论提供了一个未来的路线图，强调了元光学驱动集成在芯片级智能视觉感知方面的潜力，通过弥合硬件和软件的鸿沟，使小型化设备具有实时适应性、大规模并行性和能源效率。

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引用次数: 0

Mechanical control of the insect extracellular matrix nanostructure 昆虫细胞外基质纳米结构的机械控制

IF 12.5 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Advances

Pub Date : 2026-01-02 DOI: 10.1126/sciadv.adw5022

Yuki Itakura, Housei Wada, Sachi Inagaki, Shigeo Hayashi

Nanoscale modifications of apical extracellular matrix (ECM) have created various functional surfaces with distinct physical properties, exemplified by structural coloration and superhydrophobicity in animals and plants. To reveal the mechanisms, we investigated cuticle morphogenesis in Drosophila olfactory organs, where hundreds of ~50-nanometer nanopores in the cuticle covering the olfactory neurons permit selective odorant entry. We showed that zona pellucida domain (ZPD) proteins form the cell type–specific ECM compartments before cuticle secretion, and its disruption leads to less and irregularly sized nanopores. The ZPD protein Dusky-like controls the formation of the outermost layer of the cuticle, the envelope. Trynity, Nyobe, Neo, and Morpheyus form matrices with specific mixing and sorting properties, termed “cloud ECM,” which restrict cell growth and movement. This work identifies a previously unidentified role for ZPD proteins as modular units that establish the mechanical environment essential for nanoscale ECM morphogenesis, opening a previously unexplored context for these biomimetically important structures.

细胞外基质（ECM）的纳米修饰创造了具有不同物理性质的各种功能表面，例如动物和植物的结构着色和超疏水性。为了揭示其机制，我们研究了果蝇嗅觉器官的角质层形态发生，角质层上覆盖着嗅觉神经元的数百个~50纳米的纳米孔允许气味选择性进入。我们发现，透明带结构域（ZPD）蛋白在角质层分泌前形成细胞类型特异性的ECM区室，其破坏导致更少和不规则大小的纳米孔。ZPD蛋白Dusky-like控制角质层最外层，即包膜的形成。Trynity, Nyobe， Neo和Morpheyus形成具有特定混合和分选特性的基质，称为“云ECM”，限制细胞生长和运动。这项工作确定了ZPD蛋白作为模块化单元的先前未被识别的作用，该单元建立了纳米级ECM形态发生所必需的机械环境，为这些仿生重要结构开辟了以前未被探索的背景。

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引用次数: 0

Stabilized perovskite ink for scalable coating enables high-efficiency perovskite modules 用于可扩展涂层的稳定钙钛矿油墨可实现高效钙钛矿模块

IF 12.5 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Advances

Pub Date : 2026-01-02 DOI: 10.1126/sciadv.aec0915

Yangyang Liu, Junke Wang, Tianxiao Liu, Lingyuan Wang, Yuhan Zhou, Yaoyao Zhang, Yunjie Dou, Xiaoyu Shi, He Yan, Akash Dasgupta, Henry J. Snaith, Shangshang Chen

Perovskite inks play critical roles in determining film quality and device performance, and ink stability is desired to ensure high device reproducibility. Here, we reveal the instability issue of current cesium-formamidinium lead triiodide (Cs_xFA_1−xPbI₃) inks whose aggregation and precipitation tendencies are induced by excessively strong solvent-lead-halide coordination. By modulating coordination strength between precursor salts and solvents, we identify solvent coordination-dispersion equilibrium as the governing factor for ink stability and develop a stable ink that exhibits a remarkable increase in the shelf life. It effectively tunes ink drying and film crystallization, resulting in blade-coated perovskite films with excellent uniformity and low defect density. This enhancement led to increased aperture efficiency of ambient-fabricated p-i-n perovskite modules to 23.5%. The resultant devices also exhibit high durability, and 99% of the initial PCE was retained after 1700 hours of maximum power point tracking following the ISOS-L-2 standard protocol.

钙钛矿油墨在决定薄膜质量和器件性能方面起着至关重要的作用，油墨的稳定性是确保器件高再现性的必要条件。本文揭示了当前铯-甲脒型三碘化铅（CsxFA1−xPbI3）油墨的不稳定性问题，该油墨的聚集和沉淀倾向是由溶剂-铅-卤化物配位性过强引起的。通过调节前驱盐和溶剂之间的配位强度，我们确定溶剂配位-分散平衡是油墨稳定性的控制因素，并开发出一种稳定的油墨，其货架寿命显着增加。它有效地调节油墨干燥和薄膜结晶，从而产生具有优异均匀性和低缺陷密度的叶片涂覆钙钛矿薄膜。这种增强导致环境制造的p-i-n钙钛矿组件的孔径效率提高到23.5%。由此产生的设备也具有很高的耐用性，并且在遵循iso - l -2标准协议的最大功率点跟踪1700小时后，99%的初始PCE被保留。

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引用次数: 0