JACS AuPub Date : 2026-09-28Epub Date: 2026-09-02DOI: 10.1021/jacsau.6c01252
Jun-Li Dong, Ying Dan, Xin Xu, Bei-Bei He, Yi Huang, Jing-Jing Xu, Qing-Bo Liang, Yi-Qing Li, Li Han, Xue-Shi Huang, Jing He
{"title":"Biosynthesis of Complex Phenazines Involves Dimerization and Amination Catalyzed by a Versatile Nuclear Transport Factor 2-like Superfamily Protein","authors":"Jun-Li Dong, Ying Dan, Xin Xu, Bei-Bei He, Yi Huang, Jing-Jing Xu, Qing-Bo Liang, Yi-Qing Li, Li Han, Xue-Shi Huang, Jing He","doi":"10.1021/jacsau.6c01252","DOIUrl":"https://doi.org/10.1021/jacsau.6c01252","url":null,"abstract":"<p>Phenazine naturalproducts represent a structurally diverse classof aromatic alkaloids with broad-spectrum biological activities. Amongthese compounds, phenazine dimers have attracted considerable attentionowing to their intricate molecular architectures and potent antibacterialand anticancer properties. Although the biosynthesis of the core phenazinescaffold is well characterized, the enzymatic postmodifications, especiallythose governing dimerization processes that yield structurally varieddiphenazines, remain poorly understood. In this study, we elucidatethe complete biosynthesis of diverse dimeric and aminated phenazines.Following core assembly, the flavoprotein DapS initiates postmodificationby catalyzing the C6-selective decarboxylative hydroxylation of phenazine-1,6-dicarboxylicacid (PDC). We further uncover Dap5, a nuclear transport factor 2(NTF2)-like protein, as a multifunctional enzyme that catalyzes hydroxylation,dimerization, and amination of phenazines. Strikingly, Dap5 operatesindependently of flavin or metal cofactors, instead activating oxygenby exploiting the redox cycling of its phenazine substrate withinthe enzyme–substrate complex. Structural and docking analysesbased on a modeled protein structure suggest that these reactionslikely share a common predicted active-site cavity but employ distinctresidue networks for substrate binding and catalysis. This study solvesa long-standing puzzle in the biosynthesis of dimeric phenazines anddemonstrates a unique substrate-assisted radical strategy, offeringnew insights into the evolution of multifunctional enzymes.</p>","PeriodicalId":94060,"journal":{"name":"JACS Au","volume":"6 9","pages":"5455–5464"},"PeriodicalIF":8.5,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149067477","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JACS AuPub Date : 2026-09-28Epub Date: 2026-08-20DOI: 10.1021/jacsau.6c00949
Haitao Liu, Hengde Li, Xi Chen, Saman Hamidi, Angelo H. ALL
{"title":"Transneuronal Transport of Ligand-Conjugated Upconversion Nanoparticles from the Peripheral to the Central Nervous System","authors":"Haitao Liu, Hengde Li, Xi Chen, Saman Hamidi, Angelo H. ALL","doi":"10.1021/jacsau.6c00949","DOIUrl":"https://doi.org/10.1021/jacsau.6c00949","url":null,"abstract":"<p>Despite significantadvancements in neuro-nanotechnology, the movementof nanomaterials between peripheral and central neurons for applicationssuch as cargo delivery, imaging, and tracking remains a formidablechallenge. This limitation highlights the critical necessity for developingengineered materials that can facilitate efficient intra-axonal transportand trans-synaptic translocation. In this study, we report the designand synthesis of core–shell–shell upconversion nanoparticles(CSS-UCNPs) featuring a NaYF<sub>4</sub>:YbEr core sequentially coatedwith active NaYF<sub>4</sub>:YbNd and inert NaYF<sub>4</sub> shells.To achieve neuron-specific targeting, the architecture was surface-functionalizedwith poly(ethylene glycol) (PEG)-maleimide and conjugated to the RVG29peptide (CSS-PEG-RVG29). Characterization by transmission electronmicroscopy, dynamic light scattering, and spectroscopic analyses confirmeduniform particle size (42.9 nm radius) and efficient upconversionluminescence (λ<sub>ex</sub> = 808 nm, λ<sub>em</sub> =500−575 nm). <em>In vitro</em> assays demonstratedlow cytotoxicity in Neuro2a, NSC34, and C6 cell lines at concentrationsup to 500 μg/mL, enhanced cellular uptake mediated by RVG29,and no detectable alterations in spinal neuronal action potentialfiring, as assessed by patch-clamp electrophysiology. <em>In vivo</em>, intrafascicular injection into the mouse sciatic nerve (2 mg/mL,2 μL) resulted in nanoparticle transport to the dorsal partof the spinal cord, with localization in higher regions of the centralnervous system (CNS) and cortices, as visualized by multiphoton microscopy.In contrast, control experiments utilizing scrambled RVG29-conjugatednanoparticles demonstrated negligible accumulation within the CNS.These findings establish CSS-PEG-RVG29 as a promising platform forperipheral-to-CNS cargo delivery, with broad potential applications.</p>","PeriodicalId":94060,"journal":{"name":"JACS Au","volume":"6 9","pages":"5295–5306"},"PeriodicalIF":8.5,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149071079","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Development of High-Efficiency Mitochondrial Protease Targeting Chimeras (MtPTACs) for Targeted Degradation of POLRMT and Beyond","authors":"Cong Chen, Lihua Liu, Xinnan Li, Yuning Shi, Jieya Zhou, Lijuan Huang, Liyue Zeng, Dazhi Feng, Yunyue Wang, Xinyang Nie, Quanyi Huang, Yifei Wu, Shaokang Pang, Jinyi Xu, Shengtao Xu, Hong Yao","doi":"10.1021/jacsau.6c01255","DOIUrl":"https://doi.org/10.1021/jacsau.6c01255","url":null,"abstract":"<p>Despite the broadsuccess of targeted protein degradation (TPD),achieving efficient degradation within mitochondria remains a challenge.Herein, we report a highly active degrader targeting human mitochondrialRNA polymerase (POLRMT) based on the Mitochondrial Protease TargetingChimeras (MtPTACs) strategy. The lead compound, <strong>MTP-B1</strong>, is a highly potent MtPTAC to achieve essentially complete targetdegradation (<em>D</em><sub>max</sub> > 98%) within 24h atsub-micromolar concentrations. Mechanistically, <strong>MTP-B1</strong> circumvents the compensatory transcriptional upregulation inducedby POLRMT inhibitors and sustains downstream signaling suppressionin washout assays. Remarkably, under the dosing regimens tested, <strong>MTP-B1</strong> exhibited greater <em>in vivo</em> antitumorefficacy than the co-administration of a POLRMT inhibitor and a ClpPactivator, highlighting the therapeutic potential of targeted proteindegradation in mitochondria. These findings, further supported bythe extension to a second target, dihydroorotate dehydrogenase (DHODH),provide high-efficiency MtPTACs as a powerful and generalizable modalityfor mitochondrial medicine.</p>","PeriodicalId":94060,"journal":{"name":"JACS Au","volume":"6 9","pages":"5439–5454"},"PeriodicalIF":8.5,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149071159","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JACS AuPub Date : 2026-09-28Epub Date: 2026-08-14DOI: 10.1021/jacsau.6c00935
Penghui Li, Ben Gao, Shiyang Wang, Wei Liu, Zhisen Wei, Guoyin Yin, Yuqiang Li
{"title":"Resolving Chemically Inequivalent 11B NMR Sites via Interpretable Hybrid Machine Learning","authors":"Penghui Li, Ben Gao, Shiyang Wang, Wei Liu, Zhisen Wei, Guoyin Yin, Yuqiang Li","doi":"10.1021/jacsau.6c00935","DOIUrl":"https://doi.org/10.1021/jacsau.6c00935","url":null,"abstract":"<p>Organoboron compoundsare widely used across pharmaceuticals andmaterials science, where <sup>11</sup>B NMR spectroscopy serves asa valuable tool for structural characterization. However, severe spectralline broadening induced by the quadrupolar nature of the boron nucleusoften causes signal overlap, making it exceptionally difficult toexperimentally resolve chemically inequivalent sites in complex multiboronarchitectures. While traditional density functional theory can resolvethese ambiguities, it faces prohibitive computational bottlenecks,whereas data-driven alternatives remain constrained by the scarcityof high-quality data sets. Herein, we report a manually verified,solvent-annotated <sup>11</sup>B NMR data set constructed via a largelanguage model (LLM)-assisted workflow. Interpretable machine learningidentifies a strong correlation between the <span>BCUT2D_MRLOW</span> descriptor and the boron hybridization. Integrating these ML-derivedfeatures as prior knowledge, we developed a prior-guided Graph Transformerfor accurate atom-level chemical shift prediction. Notably, the modelprovides a form of virtual spectral resolution, enabling the discriminationof chemically inequivalent boron sites that are difficult to resolveexperimentally. We further deploy the framework as an open-accessWeb tool to support the rapid structural analysis of organoboron compounds.</p>","PeriodicalId":94060,"journal":{"name":"JACS Au","volume":"6 9","pages":"5254–5263"},"PeriodicalIF":8.5,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149071052","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JACS AuPub Date : 2026-09-28Epub Date: 2026-08-19DOI: 10.1021/jacsau.6c00499
Dmytro Bratiichuk, Dominik Kolling, Irma Redzic, Marc Stierhof, Franziska Fries, Josef Zapp, Rolf Müller, Maksym Myronovskyi, Jesko Koehnke, Andriy Luzhetskyy
{"title":"Discovery and Biosynthetic Characterization of Darumycins Expand the Chemical Space of Sesterterpene Antibiotics","authors":"Dmytro Bratiichuk, Dominik Kolling, Irma Redzic, Marc Stierhof, Franziska Fries, Josef Zapp, Rolf Müller, Maksym Myronovskyi, Jesko Koehnke, Andriy Luzhetskyy","doi":"10.1021/jacsau.6c00499","DOIUrl":"https://doi.org/10.1021/jacsau.6c00499","url":null,"abstract":"<p>The global rise of antibiotic resistance poses a publichealthchallenge, emphasizing the urgent need for novel antibiotics featuringunique chemical scaffolds and mechanisms of action. Here, we reportthe discovery and characterization of darumycins, guanidine-containingpentacyclic sesterterpene antibiotics that exhibit potent activityagainst high-priority Gram-positive pathogens and mycobacteria. Thedarumycin biosynthetic gene cluster was identified through genomemining in the Actinobacterium <em>Micromonospora rubida</em> and heterologously expressed in <em>Streptomyces</em> chassis strains. Gene cluster engineering facilitated the discoveryof novel darumycin derivatives, thereby expanding the chemical diversitywithin the sesterterpene class of natural products and revealing nuancedvariations in their bioactivity. Targeted gene deletions, along withLC–MS and NMR analyses, enabled us to propose a darumycin biosyntheticpathway, further complemented by in vitro biochemical characterizationof two O-methyltransferase tailoring enzymes, DarM and DarG. The high-resolutioncrystal structure of DarM in complex with SAH provided valuable insightsinto the enzymatic mechanism and revealed a distinct architecturecompared to other methyltransferases acting on terpene scaffolds.</p>","PeriodicalId":94060,"journal":{"name":"JACS Au","volume":"6 9","pages":"4944–4955"},"PeriodicalIF":8.5,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149067502","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JACS AuPub Date : 2026-09-28Epub Date: 2026-08-26DOI: 10.1021/jacsau.6c00596
Jun Ohnuki, Kei-ichi Okazaki
{"title":"Enhanced Sampling of Protein Conformations in AlphaFold3 with Repulsive Bias in the Diffusion Generative Model","authors":"Jun Ohnuki, Kei-ichi Okazaki","doi":"10.1021/jacsau.6c00596","DOIUrl":"https://doi.org/10.1021/jacsau.6c00596","url":null,"abstract":"<p>Conformational changes in proteins are vital to theirfunctionyet remain challenging for state-of-the-art artificial intelligence,such as AlphaFold3 (AF3), to predict. It has been observed that AF3sometimes fails to capture ligand-induced conformational changes,even though it explicitly includes ligand molecules that induce suchchanges. To address this challenge, we develop an enhanced samplingscheme that leverages the diffusion-based generative model used inAF3 to predict protein structures. Interpreting the diffusion generativemodel as a stochastic sampling process analogous to molecular dynamics(MD) simulations, we introduce here a repulsive biasing potentialbetween predicted structures to explore wider conformational space.We demonstrate that the developed sampling scheme, AF3-ReD, successfullysamples multiple conformational states in the AF3 distribution, includingligand-bound conformations of motor, kinase, and transporter proteins,which are rarely captured by the default AF3 settings. Consistencywith experimentally determined structures not only at the global structurallevel but also in local ligand-binding poses confirms reliable conformationalsampling with AF3-ReD. Notably, AF3-ReD succeeded in sampling conformationalstates of transporters that were unresolved at the AF3 training cutoff.Compared to another strategy based on multiple sequence alignment(MSA), AF3-ReD predicted intermediate conformations that are relativelycloser to the stable states. Thus, AF3-ReD provides a promising approachto predicting dynamic conformational changes of proteins associatedwith ligand binding, which could be further extended to other diffusion-basedgenerative models, such as those for protein design, potentially expandingtheir accessible design space.</p>","PeriodicalId":94060,"journal":{"name":"JACS Au","volume":"6 9","pages":"5010–5024"},"PeriodicalIF":8.5,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149067518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Go-and-Stop Nanovehicles Enabled by Counterbalanced NIR Optical Engines","authors":"Jing Wang, Jingjing Li, Ming Tang, Haomin Chen, Yaxin Sun, Wenqian Chen, Yong Zhang, Xiaohui Zhu","doi":"10.1021/jacsau.6c00299","DOIUrl":"https://doi.org/10.1021/jacsau.6c00299","url":null,"abstract":"<p>Nanomotors are promisingfor diverse applications due to theirability to convert energy into directional motion. However, precisecontrol of their motion is still difficult because creating requiredasymmetric nanostructures presents significant synthetic challenges.Inspired by automotive engine control, this study reports a generalstrategy for constructing optical nanomotors with programmable motion.For the first time, this approach implements a “Go and Stop”concept, leveraging dissimilar near-infrared (NIR) responsivitiesof upconversion nanoparticle (UCNP) to accelerate (“Go”)or brake (“Stop”) motion on demand. Specifically, thenanovehicle is designed via interface-guided anisotropic growth strategy,where half of a single upconversion nanoparticle (UCNP) is coatedwith a hydrophilic silica shell containing Au nanoseeds, while theother is covered by a hydrophobic periodic mesoporous organosilica(PMO) loaded with Roussin’s black salt (RBS). This dual hydrophilic/hydrophobicdesign is also applicable to other optical materials, thus demonstratinggreat flexibility. When excited at 980 nm, blue light emitted by theUCNP activates the RBS to release nitric oxide (NO), propelling thenanomotor forward. Conversely, light at 808 nm induces gold-mediatedthermophoresis, which reduces and eventually stops NO-driven motion.Such “pull–push” effect enables the nanomotorto start, accelerate, decelerate, and stop simply by switching theexcitation light. As a proof of concept, the nanovehicle is furtherused to noninvasively regulate cellular endocytosis and has demonstratedgreat potentials for programmable tumor treatment.</p>","PeriodicalId":94060,"journal":{"name":"JACS Au","volume":"6 9","pages":"4910–4921"},"PeriodicalIF":8.5,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149067548","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Lysine-Targeting Covalent Inhibition of Glutaminase Using Cyanopyrimidines","authors":"Xiwen Xiao, Hibiki Okuno, Saki Inoue, Naoki Zenmyo, Yuya Matsumoto, Emi Mishiro-Sato, Keiko Kano, Kazuaki Yoshimune, Shohei Uchinomiya, Akio Ojida","doi":"10.1021/jacsau.6c00924","DOIUrl":"https://doi.org/10.1021/jacsau.6c00924","url":null,"abstract":"<p>Aberrant metabolicactivity is a hallmark of cancer and is recognizedas a promising target for cancer therapy. However, covalent inhibitorsthat irreversibly modulate cancer-associated metabolic states remainlargely unexplored. Here, we report the development of covalent inhibitorstargeting glutaminase 1 (GLS1), a rate-determining enzyme in the glutaminemetabolism. To develop covalent inhibitors of GLS1, we systematicallyevaluated the reactivity of <em>N</em>-heteroaryl nitrilesand identified 2-cyanopyrimidine as a lysine-reactive electrophilesuitable for selective covalent protein targeting. A covalent inhibitorbearing a 2-cyanopyrimidine irreversibly binds GLS1 in cancer cellswith excellent proteome-wide selectivity. This mode of action effectivelysuppresses glutamine metabolism and induces death of glutamine-dependentcancer cells, highlighting the therapeutic potential of covalent targetingof GLS1.</p>","PeriodicalId":94060,"journal":{"name":"JACS Au","volume":"6 9","pages":"5243–5253"},"PeriodicalIF":8.5,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149067478","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JACS AuPub Date : 2026-09-28Epub Date: 2026-09-10DOI: 10.1021/jacsau.6c01053
Leonard Kersting, Judith Braunreuther, Erika Linde, Berit Olofsson
{"title":"SNAr-Functionalization of Diaryliodonium Salts: Access to Densely Substituted Arenes","authors":"Leonard Kersting, Judith Braunreuther, Erika Linde, Berit Olofsson","doi":"10.1021/jacsau.6c01053","DOIUrl":"https://doi.org/10.1021/jacsau.6c01053","url":null,"abstract":"<p>Diaryliodonium salts are efficient electrophilic arylationreagentsfor a wide variety of nucleophiles. The main limitation in the arylationscope is often the difficulty in synthesizing advanced heteroatom-functionalizeddiaryliodonium salts, due to their sensitivity to acidic and oxidativeconditions. We present a general S<sub>N</sub>Ar strategy to functionalizefluoro-substituted iodonium salts, which enables the synthesis ofa wide range of heteroatom-functionalized iodonium salts, with demonstratedreactivity in a variety of transition-metal-free <em>O-</em>, <em>N-</em>, and <em>S</em>-arylations to providedensely functionalized aromatic products.</p>","PeriodicalId":94060,"journal":{"name":"JACS Au","volume":"6 9","pages":"5395–5400"},"PeriodicalIF":8.5,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149067613","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JACS AuPub Date : 2026-09-28Epub Date: 2026-07-31DOI: 10.1021/jacsau.6c00796
Sudripet Sharma, Uyen Duong, Maarten Nachtegaal, Adam H. Clark, Ramesh Hiralal Choudhary, Jacek B. Jasinski, Wilfried Braje, Sachin Handa
{"title":"On-Cycle Enforcement in Water: Trimetallic Assemblies Preventing Pd Black Formation While Accelerating Selective Suzuki–Miyaura Coupling without Olefin Interference","authors":"Sudripet Sharma, Uyen Duong, Maarten Nachtegaal, Adam H. Clark, Ramesh Hiralal Choudhary, Jacek B. Jasinski, Wilfried Braje, Sachin Handa","doi":"10.1021/jacsau.6c00796","DOIUrl":"https://doi.org/10.1021/jacsau.6c00796","url":null,"abstract":"<p>Palladium-catalyzed cross-couplings are frequently limitedby off-cycledeactivation pathways, particularly phosphine deligation followedby aggregation of Pd(0) to catalytically inactive palladium black.We report an “on-cycle enforcement” strategy that employsa cooperative, nonalloyed trimetallic assembly─Pd(0), Cu(I),and Mn(III)─confined within PS-750-M/HPMC micelles in water.In this architecture, Pd mediates the canonical oxidative additionand reductive elimination steps, Cu(I) accelerates transmetalationvia a Cu-nucleophile intermediate, and Mn(II/III) serves as a redoxbuffer that likely continuously reoxidizes off-cycle Pd(0) to micelle-solublePd(II), followed by its religation and reduction, thereby preventingPd black formation. Spectroscopic analysis─transmission electronmicroscopy, scanning transmission electron microscopy–high-angleannular dark-field imaging, energy-dispersive X-ray spectroscopy,X-ray photoelectron spectroscopy, and X-ray absorption spectroscopy─revealsthat the three metals remain spatially separated in the assembly yetelectronically complementary within a phosphorus-rich matrix, enablingpersistent catalytic activity. The resulting platform supports rapid,selective C–C couplings at 45 °C with broad substratecompatibility, including heteroarenes and terminal olefin─containingpartners, without olefin interference. The catalyst displays exceptionallongevity, minimal metal leaching (<1 ppm), and robust scalability,with multicycle reactions and gram-scale processes proceeding efficientlyeven after extended catalyst storage. These findings establish redox-buffered,compartmentalized trimetallic assemblies as a general solution toenforcing on-cycle Pd catalysis in water.</p>","PeriodicalId":94060,"journal":{"name":"JACS Au","volume":"6 9","pages":"5145–5153"},"PeriodicalIF":8.5,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149067571","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}