Activation of γ-globin expression by hypoxia-inducible factor 1α.

Around birth, globin expression in human red blood cells (RBCs) shifts from γ-globin to ß-globin, which results in fetal haemoglobin (HbF, α2γ2) being gradually replaced by adult haemoglobin (HbA, α2ß2)1. This process has motivated the development of innovative approaches to treat sickle cell disease and ß-thalassaemia by increasing HbF levels in postnatal RBCs2. Here we provide therapeutically relevant insights into globin gene switching obtained through a CRISPR-Cas9 screen for ubiquitin-proteasome components that regulate HbF expression. In RBC precursors, depletion of the von Hippel-Lindau (VHL) E3 ubiquitin ligase stabilized its ubiquitination target, hypoxia-inducible factor 1α (HIF1α)3,4, to induce γ-globin gene transcription. Mechanistically, HIF1α-HIF1ß heterodimers bound cognate DNA elements in BGLT3, a long noncoding RNA gene located 2.7 kb downstream of the tandem γ-globin genes HBG1 and HBG2. This was followed by the recruitment of transcriptional activators, chromatin opening and increased long-range interactions between the γ-globin genes and their upstream enhancer. Similar induction of HbF occurred with hypoxia or with inhibition of prolyl hydroxylase domain enzymes that target HIF1α for ubiquitination by the VHL E3 ubiquitin ligase. Our findings link globin gene regulation with canonical hypoxia adaptation, provide a mechanism for HbF induction during stress erythropoiesis and suggest a new therapeutic approach for ß-haemoglobinopathies.

Independent origins of fetal liver haematopoietic stem and progenitor cells.

Self-renewal and differentiation are tightly controlled to maintain haematopoietic stem cell (HSC) homeostasis in the adult bone marrow1,2. During fetal development, expansion of HSCs (self-renewal) and production of differentiated haematopoietic cells (differentiation) are both required to sustain the haematopoietic system for body growth3,4. However, it remains unclear how these two seemingly opposing tasks are accomplished within the short embryonic period. Here we used in vivo genetic tracing in mice to analyse the formation of HSCs and progenitors from intra-arterial haematopoietic clusters, which contain HSC precursors and express the transcription factor hepatic leukaemia factor (HLF). Through kinetic study, we observed the simultaneous formation of HSCs and defined progenitors-previously regarded as descendants of HSCs5-from the HLF+ precursor population, followed by prompt formation of the hierarchical haematopoietic population structure in the fetal liver in an HSC-independent manner. The transcription factor EVI1 is heterogeneously expressed within the precursor population, with EVI1hi cells being predominantly localized to intra-embryonic arteries and preferentially giving rise to HSCs. By genetically manipulating EVI1 expression, we were able to alter HSC and progenitor output from precursors in vivo. Using fate tracking, we also demonstrated that fetal HSCs are slowly used to produce short-term HSCs at late gestation. These data suggest that fetal HSCs minimally contribute to the generation of progenitors and functional blood cells before birth. Stem cell-independent pathways during development thus offer a rational strategy for the rapid and simultaneous growth of tissues and stem cell pools.

Interspecies regulatory landscapes and elements revealed by novel joint systematic integration of human and mouse blood cell epigenomes.

Knowledge of locations and activities of cis-regulatory elements (CREs) is needed to decipher basic mechanisms of gene regulation and to understand the impact of genetic variants on complex traits. Previous studies identified candidate CREs (cCREs) using epigenetic features in one species, making comparisons difficult between species. In contrast, we conducted an interspecies study defining epigenetic states and identifying cCREs in blood cell types to generate regulatory maps that are comparable between species, using integrative modeling of eight epigenetic features jointly in human and mouse in our Validated Systematic Integration (VISION) Project. The resulting catalogs of cCREs are useful resources for further studies of gene regulation in blood cells, indicated by high overlap with known functional elements and strong enrichment for human genetic variants associated with blood cell phenotypes. The contribution of each epigenetic state in cCREs to gene regulation, inferred from a multivariate regression, was used to estimate epigenetic state regulatory potential (esRP) scores for each cCRE in each cell type, which were used to categorize dynamic changes in cCREs. Groups of cCREs displaying similar patterns of regulatory activity in human and mouse cell types, obtained by joint clustering on esRP scores, harbor distinctive transcription factor binding motifs that are similar between species. An interspecies comparison of cCREs revealed both conserved and species-specific patterns of epigenetic evolution. Finally, we show that comparisons of the epigenetic landscape between species can reveal elements with similar roles in regulation, even in the absence of genomic sequence alignment.

Tissue-specific mitotic bookmarking by hematopoietic transcription factor GATA1.

Tissue-specific transcription patterns are preserved throughout cell divisions to maintain lineage fidelity. We investigated whether transcription factor GATA1 plays a role in transmitting hematopoietic gene expression programs through mitosis when transcription is transiently silenced. Live-cell imaging revealed that a fraction of GATA1 is retained focally within mitotic chromatin. ChIP-seq of highly purified mitotic cells uncovered that key hematopoietic regulatory genes are occupied by GATA1 in mitosis. The GATA1 coregulators FOG1 and TAL1 dissociate from mitotic chromatin, suggesting that GATA1 functions as platform for their postmitotic recruitment. Mitotic GATA1 target genes tend to reactivate more rapidly upon entry into G1 than genes from which GATA1 dissociates. Mitosis-specific destruction of GATA1 delays reactivation selectively of genes that retain GATA1 during mitosis. These studies suggest a requirement of mitotic "bookmarking" by GATA1 for the faithful propagation of cell-type-specific transcription programs through cell division.

Personal omics profiling reveals dynamic molecular and medical phenotypes.

Personalized medicine is expected to benefit from combining genomic information with regular monitoring of physiological states by multiple high-throughput methods. Here, we present an integrative personal omics profile (iPOP), an analysis that combines genomic, transcriptomic, proteomic, metabolomic, and autoantibody profiles from a single individual over a 14 month period. Our iPOP analysis revealed various medical risks, including type 2 diabetes. It also uncovered extensive, dynamic changes in diverse molecular components and biological pathways across healthy and diseased conditions. Extremely high-coverage genomic and transcriptomic data, which provide the basis of our iPOP, revealed extensive heteroallelic changes during healthy and diseased states and an unexpected RNA editing mechanism. This study demonstrates that longitudinal iPOP can be used to interpret healthy and diseased states by connecting genomic information with additional dynamic omics activity.

Synthesis of paracrystalline diamond.

Solids in nature can be generally classified into crystalline and non-crystalline states1-7, depending on whether long-range lattice periodicity is present in the material. The differentiation of the two states, however, could face fundamental challenges if the degree of long-range order in crystals is significantly reduced. Here we report a paracrystalline state of diamond that is distinct from either crystalline or amorphous diamond8-10. The paracrystalline diamond reported in this work, consisting of sub-nanometre-sized paracrystallites that possess a well-defined crystalline medium-range order up to a few atomic shells4,5,11-13, was synthesized in high-pressure high-temperature conditions (for example, 30 GPa and 1,600 K) employing face-centred cubic C60 as a precursor. The structural characteristics of the paracrystalline diamond were identified through a combination of X-ray diffraction, high-resolution transmission microscopy and advanced molecular dynamics simulation. The formation of paracrystalline diamond is a result of densely distributed nucleation sites developed in compressed C60 as well as pronounced second-nearest-neighbour short-range order in amorphous diamond due to strong sp3 bonding. The discovery of paracrystalline diamond adds an unusual diamond form to the enriched carbon family14-16, which exhibits distinguishing physical properties and can be furthered exploited to develop new materials. Furthermore, this work reveals the missing link in the length scale between amorphous and crystalline states across the structural landscape, having profound implications for recognizing complex structures arising from amorphous materials.

Activating Metal-Organic Cages by Incorporating Functional M(ImPhen)3 Metalloligands: From Structural Design to Applications.

ConspectusThe emulation of ingenious biofunctions has been a research focus for several decades. Metal-organic cages (MOCs), as a type of discrete supramolecular assembly with well-defined shapes and cavities, have aroused great interest in chemists to imitate natural protein cages or enzymes. However, to genuinely achieve tailored functionalities or reactivities of enzymes, the design of cage structures combining both the confined microenvironment and the active site is a prerequisite. Therefore, the integration of functionalized motifs into MOCs is expected to provide a feasible approach to construct biofunctional confined nanospaces, which not only allows the modulation of cage properties for applications such as molecular recognition, transport, and catalysis but also creates unique microenvironments that promote enzymatic effects for special reactivities and selectivities, thereby providing a versatile platform to achieve exceptional biomimetic functions and beyond.In this Account, we specifically focus on our research toward engineering active confined-nanospaces in MOCs via incorporation of M(ImPhen)3 metalloligands, a typical tris-chelate coordination moiety comprising imidazophenanthroline ligands and variable metal ions, as the principle functional units for stepwise assembly of active-MOCs. Starting from their structure design and merits, we describe the versatility of M(ImPhen)3 centers for multifunctionalization of the confined cage-nanospaces. By integrating different metal ions like Ru, Os, Fe, Co, Ni, Zn, the metal ion inherent properties, e.g., redox activity of Fe/Co-centers, chirality, and photoactivity of Ru-centers, and dynamics of Co/Zn-centers, could be integrated and tailored on the cages as isostructural nanosized containers or reactors. Changing the Pd or Pt cage vertices to organic clips could remarkably enhance acid-base stability and endow cages with flexibility and allostery. Utilization of ImPhen organic ligands containing imidazole groups introduces proton transfer capability, which can couple with the high-positive charges on the cage to create amphoteric microenvironments in the porous open-cage solution. Moreover, the nonplanar stereoconfiguration of M(ImPhen)3 confers multiple peripheral pockets on the cage, which render multisite, high-order, and dynamics guest binding for the benefit of applications such as drug delivery, molecular separation, and catalytic turnover.The construction of active-MOCs from tailorable M(ImPhen)3 metalloligands provides us with a new perspective on their structural design and functionalities. Merging the cage confinement with distinct physicochemical properties on a supramolecular level makes it practical to realize synergistic and cooperative effects for functionality enhancement beyond molecular components or the reactivity different from the bulky solution, which could largely expand the potential of MOCs as a multirole platform to wide application scenarios such as artificial photosynthesis, unconventional catalysis, and theranostic nanomedicine.

Prolonged myelin deficits contribute to neuron loss and functional impairments after ischaemic stroke.

Ischaemic stroke causes neuron loss and long-term functional deficits. Unfortunately, effective approaches to preserving neurons and promoting functional recovery remain unavailable. Oligodendrocytes, the myelinating cells in the CNS, are susceptible to oxygen and nutrition deprivation and undergo degeneration after ischaemic stroke. Technically, new oligodendrocytes and myelin can be generated by the differentiation of oligodendrocyte precursor cells (OPCs). However, myelin dynamics and their functional significance after ischaemic stroke remain poorly understood. Here, we report numerous denuded axons accompanied by decreased neuron density in sections from ischaemic stroke lesions in human brain, suggesting that neuron loss correlates with myelin deficits in these lesions. To investigate the longitudinal changes in myelin dynamics after stroke, we labelled and traced pre-existing and newly-formed myelin, respectively, using cell-specific genetic approaches. Our results indicated massive oligodendrocyte death and myelin loss 2 weeks after stroke in the transient middle cerebral artery occlusion (tMCAO) mouse model. In contrast, myelin regeneration remained insufficient 4 and 8 weeks post-stroke. Notably, neuronal loss and functional impairments worsened in aged brains, and new myelin generation was diminished. To analyse the causal relationship between remyelination and neuron survival, we manipulated myelinogenesis by conditional deletion of Olig2 (a positive regulator) or muscarinic receptor 1 (M1R, a negative regulator) in OPCs. Deleting Olig2 inhibited remyelination, reducing neuron survival and functional recovery after tMCAO. Conversely, enhancing remyelination by M1R conditional knockout or treatment with the pro-myelination drug clemastine after tMCAO preserved white matter integrity and neuronal survival, accelerating functional recovery. Together, our findings demonstrate that enhancing myelinogenesis is a promising strategy to preserve neurons and promote functional recovery after ischaemic stroke.

Metabolic heterogeneity underlies reciprocal fates of TH17 cell stemness and plasticity.

A defining feature of adaptive immunity is the development of long-lived memory T cells to curtail infection. Recent studies have identified a unique stem-like T-cell subset amongst exhausted CD8-positive T cells in chronic infection1-3, but it remains unclear whether CD4-positive T-cell subsets with similar features exist in chronic inflammatory conditions. Amongst helper T cells, TH17 cells have prominent roles in autoimmunity and tissue inflammation and are characterized by inherent plasticity4-7, although how such plasticity is regulated is poorly understood. Here we demonstrate that TH17 cells in a mouse model of autoimmune disease are functionally and metabolically heterogeneous; they contain a subset with stemness-associated features but lower anabolic metabolism, and a reciprocal subset with higher metabolic activity that supports transdifferentiation into TH1-like cells. These two TH17-cell subsets are defined by selective expression of the transcription factors TCF-1 and T-bet, and by discrete levels of CD27 expression. We also identify signalling via the kinase complex mTORC1 as a central regulator of TH17-cell fate decisions by coordinating metabolic and transcriptional programmes. TH17 cells with disrupted mTORC1 signalling or anabolic metabolism fail to induce autoimmune neuroinflammation or to develop into TH1-like cells, but instead upregulate TCF-1 expression and acquire stemness-associated features. Single-cell RNA sequencing and experimental validation reveal heterogeneity in fate-mapped TH17 cells, and a developmental arrest in the TH1 transdifferentiation trajectory upon loss of mTORC1 activity or metabolic perturbation. Our results establish that the dichotomy of stemness and effector function underlies the heterogeneous TH17 responses and autoimmune pathogenesis, and point to previously unappreciated metabolic control of plasticity in helper T cells.

Comprehensive review of indicators and techniques for optical mapping of intracellular calcium ions.

Calcium ions (Ca2+) play crucial roles in almost every cellular process, making the detection of changes in intracellular Ca2+ essential to understanding cell function. The fluorescence indicator method has garnered widespread application due to its exceptional sensitivity, rapid analysis, cost-effectiveness, and user-friendly nature. It has successfully delineated the spatial and temporal dynamics of Ca2+ signaling across diverse cell types. However, it is vital to understand that different indicators have varying levels of accuracy, sensitivity, and stability, making choosing the right inspection method crucial. As optical detection technologies advance, they continually broaden the horizons of scientific inquiry. This primer offers a systematic synthesis of the current fluorescence indicators and optical imaging modalities utilized for the detection of intracellular Ca2+. It elucidates their practical applications and inherent limitations, serving as an essential reference for researchers seeking to identify the most suitable detection methodologies for their calcium-centric investigations.

Development and IND-enabling studies of a novel Cas9 genome-edited autologous CD34+ cell therapy to induce fetal hemoglobin for sickle cell disease.

Sickle cell disease (SCD) is a common, severe genetic blood disorder. Current pharmacotherapies are partially effective and allogeneic hematopoietic stem cell transplantation is associated with immune toxicities. Genome editing of patient hematopoietic stem cells (HSCs) to reactivate fetal hemoglobin (HbF) in erythroid progeny offers an alternative potentially curative approach to treat SCD. Although the FDA released guidelines for evaluating genome editing risks, it remains unclear how best to approach pre-clinical assessment of genome-edited cell products. Here, we describe rigorous pre-clinical development of a therapeutic γ-globin gene promoter editing strategy that supported an investigational new drug application cleared by the FDA. We compared γ-globin promoter and BCL11A enhancer targets, identified a potent HbF-inducing lead candidate, and tested our approach in mobilized CD34+ hematopoietic stem progenitor cells (HSPCs) from SCD patients. We observed efficient editing, HbF induction to predicted therapeutic levels, and reduced sickling. With single-cell analyses, we defined the heterogeneity of HbF induction and HBG1/HBG2 transcription. With CHANGE-seq for sensitive and unbiased off-target discovery followed by targeted sequencing, we did not detect off-target activity in edited HSPCs. Our study provides a blueprint for translating new ex vivo HSC genome editing strategies toward clinical trials for treating SCD and other blood disorders.

Electronic and Transport Properties of InSe/PtTe2 van der Waals Heterostructure.

Two-dimensional (2D) InSe and PtTe2 have drawn extensive attention due to their intriguing properties. However, the InSe monolayer is an indirect bandgap semiconductor with a low hole mobility. van der Waals (vdW) heterostructures produce interesting electronic and optoelectronic properties beyond the existing 2D materials and endow totally new device functions. Herein, we theoretically investigated the electronic structures, transport behaviors, and electric field tuning effects of the InSe/PtTe2 vdW heterostructures. The calculated results show that the direct bandgap type-II vdW heterostructures can be realized by regulating the stacking configurations of heterostructures. By applying an external electric field, the band alignment and bandgap of the heterostructures can also be flexibly modulated. Particularly, the hole mobility of the heterostructures is improved by 2 orders of magnitude to ∼103 cm2 V-1 s-1, which overcomes the intrinsic disadvantage of the InSe monolayer. The InSe/PtTe2 vdW heterostructures have great potential applications in developing novel optoelectronic devices.

Mycobacterium abscessus extracellular vesicles increase mycobacterial resistance to clarithromycin in vitro.

Nontuberculous Mycobacteria (NTM) are a group of emerging bacterial pathogens that have been identified in cystic fibrosis (CF) patients with microbial lung infections. The treatment of NTM infection in CF patients is challenging due to the natural resistance of NTM species to many antibiotics. Mycobacterium abscessus is one of the most common NTM species found in the airways of CF patients. In this study, we characterized the extracellular vesicles (EVs) released by drug-sensitive M. abscessus untreated or treated with clarithromycin (CLR), one of the frontline anti-NTM drugs. Our data show that exposure to CLR increases mycobacterial protein trafficking into EVs as well as the secretion of EVs in culture. Additionally, EVs released by CLR-treated M. abscessus increase M. abscessus resistance to CLR when compared to EVs from untreated M. abscessus. Proteomic analysis further indicates that EVs released by CLR-treated M. abscessus carry an increased level of 50S ribosomal subunits, the target of CLR. Taken together, our results suggest that EVs play an important role in M. abscessus resistance to CLR treatment.

Characterization of Exosomes Released from Mycobacterium abscessus-Infected Macrophages.

Extracellular vesicles (EVs), such as exosomes, play a critical role in cell-to-cell communication and regulating cellular processes in recipient cells. Non-tuberculous mycobacteria (NTM), such as Mycobacterium abscessus, are a group of environmental bacteria that can cause severe lung infections in populations with pre-existing lung conditions, such as cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). There is limited knowledge of the engagement of EVs in the host-pathogen interactions in the context of NTM infections. In this study, we found that M. abscessus infection increased the release of a subpopulation of exosomes (CD9, CD63, and/or CD81 positive) by mouse macrophages in cell culture. Proteomic analysis of these vesicles demonstrated that M. abscessus infection affects the enrichment of host proteins in exosomes released by macrophages. When compared to exosomes from uninfected macrophages, exosomes released by M. abscessus-infected macrophages significantly improved M. abscessus growth and downregulated the intracellular level of glutamine in recipient macrophages in cell culture. Increasing glutamine concentration in the medium rescued intracellular glutamine levels and M. abscessus killing in recipient macrophages that were treated with exosomes from M. abscessus-infected macrophages. Taken together, our results indicate that exosomes may serve as extracellular glutamine eliminators that interfere with glutamine-dependent M. abscessus killing in recipient macrophages.

Insights into Ganoderma fungi meroterpenoids opening a new era of racemic natural products in mushrooms.

Ganoderma meroterpenoids (GMs) containing 688 structures to date were discovered to have multiple remarkable biological activities. 65.6% of meroterpenoids featuring stereogenic centers from Ganoderma species are racemates. Further, GMs from different Ganoderma species seem to have their own characteristics. In this review, a comprehensive summarization of GMs since 2000 is presented, including GM structures, structure corrections, biological activities, physicochemical properties, total synthesis, and proposed biosynthetic pathways. Additionally, we especially discuss the racemic nature, species-related structural distribution, and structure-activity relationship of GMs, which will provide a likely in-house database and shed light on future studies on GMs.

Multipocket Cage Enables the Binding of High-Order Bulky and Drug Guests Uncovered by MS Methodology.

Achieving high guest loading and multiguest-binding capacity holds crucial significance for advancement in separation, catalysis, and drug delivery with synthetic receptors; however, it remains a challenging bottleneck in characterization of high-stoichiometry guest-binding events. Herein, we describe a large-sized coordination cage (MOC-70-Zn8Pd6) possessing 12 peripheral pockets capable of accommodating multiple guests and a high-resolution electrospray ionization mass spectrometry (HR-ESI-MS)-based method to understand the solution host-guest chemistry. A diverse range of bulky guests, varying from drug molecules to rigid fullerenes as well as flexible host molecules of crown ethers and calixarenes, could be loaded into open pockets with high capacities. Notably, these hollow cage pockets provide multisites to capture different guests, showing heteroguest coloading behavior to capture binary, ternary, or even quaternary guests. Moreover, a pair of commercially applied drugs for the combination therapy of chronic lymphocytic leukemia (CLL) has been tested, highlighting its potential in multidrug delivery for combined treatment.

Stereochemical Control of Redox CoII/CoIII-Cages with Switchable Cotton Effects Based on Labile-Static States.

The structural dynamics of artificial assemblies, in aspects such as molecular recognition and structural transformation, provide us with a blueprint to achieve bioinspired applications. Here, we describe the assembly of redox-switchable chiral metal-organic cages Λ8/Δ8-[Pd6(CoIIL3)8]28+ and Λ8/Δ8-[Pd6(CoIIIL3)8]36+. These isomeric cages demonstrate an on-off chirality logic gate controlled by their chemical and stereostructural dynamics tunable through redox transitions between the labile CoII-state and static CoIII-state with a distinct Cotton effect. The transition between different states is enabled by a reversible redox process and chiral recognition originating in the tris-chelate Co-centers. All cages in two states are thoroughly characterized by NMR, ESI-MS, CV, CD, and X-ray crystallographic analysis, which clarify their redox-switching behaviors upon chemical reduction/oxidation. The stereochemical lability of the CoII-center endows the Λ8/Δ8-CoII-cages with efficient chiral-induction by enantiomeric guests, leading to enantiomeric isomerization to switch between Λ8/Δ8-CoII-cages, which can be stabilized by oxidation to their chemically inert forms of Λ8/Δ8-CoIII-cages. Kinetic studies reveal that the isomerization rate of the Δ8-CoIII-cage is at least an order of magnitude slower than that of the Δ8-CoII-cage even at an elevated temperature, while its activation energy is 16 kcal mol-1 higher than that of the CoII-cage.

Linker-Guided Growth of Single-Crystal Covalent Organic Frameworks.

The core features of covalent organic frameworks (COFs) are crystallinity and porosity. However, the synthesis of single-crystal COFs with monomers of diverse reactivity and adjustment of their pore structures remain challenging. Here, we show that linkers that can react with a node to form single-crystal COFs can guide other linkers that form either COFs or amorphous polymers with the node to gain single-crystal COFs with mixed components, which are homogeneous on the unit cell scale with controlled ratios. With the linker-guided crystal growth method, we created nine types of single-crystal COFs with up to nine different components, which are more complex than any known crystal. The structure of the crystal adapted approximately to that of the main component, and its pore volume could be expanded up to 8.8%. Different components lead to complex and diverse pore structures and offer the possibilities to gain positive synergies, as exemplified by a bicomponent COF with 2200 and 733% SO2 uptake capacity of that of the two pure-component counterparts at 298 K and 0.002 bar. The selectivity for separation of SO2/CO2 ranges from 1230 to 4247 for flue gas based on ideal adsorbed solution theory, recording porous crystals. The bicomponent COF also exhibits a 1300% retention time of its pure-component counterparts for SO2 in a dynamic column breakthrough experiment for deep desulfurization.

Medicinal plant resin natural products: structural diversity and biological activities.

Covering: up to the mid of 2023Plants secrete defense resins rich in small-molecule natural products under abiotic and biotic stresses. This comprehensive review encompasses the literature published up to mid-2023 on medicinal plant resin natural products from six main contributor genera, featuring 275 citations that refer to 1115 structurally diverse compounds. The scope of this review extends to include essential information such as the racemic nature of metabolites found in different species of plant resins, source of resins, and revised structures. Additionally, we carefully analyze the reported biological activities of resins, organizing them based on the their structures. The findings offer important insights into the relationship between their structure and activity. Furthermore, this detailed examination can be valuable for researchers and scientists in the field of medicinal plant resin natural products and will promote continued exploration and progress in this area.

Electrolyte Engineering with TFA- Anion-Rich Solvation Structure to Construct Highly Stable Zn2+/Na+ Dual-Salt Batteries.

Electrolyte engineering is recognized as an effective technique for high-performance aqueous zinc-ion rechargeable batteries, addressing difficulties such as free water decomposition, zinc anode corrosion, and zinc dendrite growth. Different from traditional strategies in aqueous electrolyte systems, this work focuses on organic electrolytes involving zinc trifluoroacetate hydrate (Zn(TFA)2·xH2O), sodium trifluoroacetate (NaTFA) dual-salt and acetonitrile (AN) solvent, in which trifluoroacetate anions (TFA- anions) have strong affinity toward zinc ions to form anion-rich solvates, thus inducing an inorganic-rich solid electrolyte interphase (SEI) to protect Zn from dendrite growth and side reactions. The Zn anode manifests long-term cycling over 2400 h at a current density of 0.5 mA cm-2 with a high Coulombic efficiency (CE) of 99.75%, showing an areal capacity as high as 5 mAh cm-2. Owing to the high reversibility of the sodium ions intercalation/deintercalation process in Na2MnFe(CN)6, the Zn//Na2MnFe(CN)6 full cells with the dual-salt electrolyte perform much better in terms of capacity retention than a device with Zn(TFA)2/AN electrolyte. This approach may open a new avenue for efficient zinc-ion rechargeable batteries via developing organic electrolytes.