Achieving pancreatic-targeted delivery marks a breakthrough in treating pancreatic diseases, yet precise delivery remains challenging1. Here we identify an explicit and universal principle for pancreatic-selective delivery and propose a pancreatic-targeted lipid nanoparticle (AH-LNP) for mRNA delivery. AH-LNP exhibits size enlargement after assembly with proteins, facilitating capsule-filter-mediated pancreas-selective accumulation and receptor-mediated endocytosis, thereby boosting the pancreatic-targeted ability. Benefiting from this, AH-LNP enables precise and efficient genome editing in the pancreas through the delivery of Cas9 mRNA and single guide RNA (sgRNA), exhibiting promising potential in the treatment of autoimmune pancreatic diseases. Furthermore, pancreatic-targeted delivery of mRNA encoding therapeutic cytokines through AH-LNP demonstrates superior antitumour efficacy when combined with a cancer vaccine or chimeric antigen receptor T cell therapy in multiple pancreatic cancer models. The safety and pancreatic mRNA delivery of AH-LNP were verified in multiple animal models, including non-human primates, demonstrating great promise for clinical translation. Our findings highlight the transformative potential of this pancreatic-targeted mechanism and the derived LNP platform, opening avenues for developing precision therapeutics against diverse pancreatic diseases.

The family of nickelate superconductors have long been explored as analogues of the high-temperature cuprates1-6. Nonetheless, the recent discovery that certain stoichiometric nickelates superconduct up to high critical temperatures (Tc) under pressure came as a surprise7-13. The mechanisms underlying the superconducting state remain experimentally unclear. Apart from the practical challenges posed by working in a high-pressure environment, typical samples exhibit anomalously weak diamagnetic responses, which have been conjectured to reflect inhomogeneous 'filamentary' superconducting states7,9,14-17. Here we perform wide-field, high-pressure, optically detected magnetic resonance spectroscopy to image the local diamagnetic responses of as-grown La3Ni2O7 samples in situ, using nitrogen vacancy quantum sensors embedded in the diamond anvil cell18-23. These maps confirm marked inhomogeneity of the functional superconducting responses at the few μm scale. By spatially correlating the diamagnetic Meissner response with both the local tensorial stress environment, also imaged in situ, and stoichiometric composition, we show the dominant mechanisms suppressing and enhancing superconductivity. Our wide-field technique simultaneously provides a broad view of sample behaviour and excellent local sensitivity, enabling the rapid construction of multi-parameter phase diagrams from the local structure-function correlations observed at the sub-μm pixel scale.

From mammals to bacteria, the direct recognition and cleavage of viral nucleic acids is a potent defence strategy against viral infection, but it requires mechanisms for distinguishing self from non-self1,2. In bacteria, CRISPR-Cas and restriction-modification systems achieve this discrimination by recognizing specific DNA sequences or DNA modifications, respectively. Alternative mechanisms probably remain to be discovered. Here, we characterize SNIPE, an anti-bacteriophage defence system that constitutively localizes to the bacterial cell membrane in Escherichia coli to block phage λ infection. Using radiolabelled phage DNA and time-lapse microscopy to track phage genomes, we demonstrate that SNIPE directly cleaves phage DNA during genome injection. Based on proximity labelling, we find that SNIPE associates with host proteins essential for λ genome entry and with the λ tape measure protein, which facilitates λ genome injection across the inner membrane. SNIPE also defends against diverse siphoviruses, probably through direct interactions with their tape measure proteins. Our findings establish SNIPE as a widespread bacterial defence system that exploits the spatial organization of phage genome injection to specifically target viral DNA, representing a previously unknown strategy for distinguishing self from non-self in prokaryotic immune systems.

The sensitivity of non-local optical measurements at low light intensities, such as those involved in long-baseline telescope arrays1,2, is limited by fundamental quantum noise and photon losses3. Distributed quantum entanglement has been proposed as a route towards overcoming these limitations and accessing new regimes of non-local optical sensing4-6. Here we demonstrate the use of entangled quantum memories in a quantum network of silicon-vacancy centres in diamond nanocavities7-9 to experimentally perform such non-local phase measurements. Specifically, we combine the generation of event-ready remote quantum entanglement, photon mode erasure that hides the 'which-path' information of temporally and spatially separated incoming optical modes and non-local, non-destructive photon heralding enabled by remote entanglement to perform a proof-of-concept entanglement-assisted differential phase measurement of weak incident light between two spatially separate stations. Demonstrating successful operation of the remote phase sensing protocol with a fibre link baseline up to 1.55 km, our results provide an opportunity for a new class of quantum-enhanced optical imaging methods with potential applications ranging from long-baseline interferometry and astronomy to microscopy10,11.

Biological machines use targeted deformations that can be actuated by Brownian fluctuations. However, although synthetic micromachines can similarly make use of targeted deformations, they are too stiff to be driven by thermal fluctuations and require strong forcing1-3. Furthermore, systems that are able to change their conformation by thermal fluctuations do so uncontrollably4,5 or require external control6. Here we use DNA-based sliding contacts7-9 to create colloidal pivots, rigid anisotropic objects that freely fluctuate around their pivot point and use a hierarchical strategy to assemble these into Brownian metamaterials with targeted deformation modes. We realize the archetypical rotating diamond and rotating triangle, or kagome, geometries and quantitatively show how thermal fluctuations drive their predicted auxetic deformations10-15. Finally, we implement magnetic particles into the colloidal pivots to achieve colloidal metamaterials that can be controlled externally as well as use Brownian fluctuations for precisely controlled shape changes. Together, our work introduces a strategy for creating Brownian mechanical metamaterials with easily actuatable deformation modes.

Vectorization of teaching signals is a key element of almost all modern machine learning algorithms, including backpropagation, target propagation and reinforcement learning. Vectorization allows a scalable and computationally efficient solution to the credit assignment problem by tailoring instructive signals to individual neurons. Recent theoretical models have suggested that neural circuits could implement single-phase vectorized learning at the cellular level by processing feedforward and feedback information streams in separate dendritic compartments1-5. This presents a compelling, but untested, hypothesis for how cortical circuits could solve credit assignment in the brain. Here we used a neurofeedback brain-computer interface task with an experimenter-defined reward function to test for vectorized instructive signals in dendrites. We trained mice to modulate the activity of two spatially intermingled populations (four or five neurons each) of layer 5 pyramidal neurons in the retrosplenial cortex to rotate a visual grating towards a target orientation while we recorded GCaMP activity from somas and corresponding distal apical dendrites. We observed that the relative magnitudes of somatic and dendritic signals could be predicted using the activity of the surrounding network and contained information about task-related variables that could serve as instructive signals, including reward and error. The signs of these putative teaching signals depended on the causal role of individual neurons in the task and predicted changes in overall activity over the course of learning. Furthermore, targeted optogenetic perturbation of these signals disrupted learning. These results demonstrate a vectorized instructive signal in the brain, implemented via semi-independent computation in cortical dendrites, unveiling a potential mechanism for solving credit assignment in the brain.

The existence of human hippocampal neurogenesis has long been disputed1-12 and its relevance in cognition remains unknown. Recent studies have established the presence of proliferating progenitors and immature neurons and a reduction in the latter in Alzheimer's disease (AD)11,13. However, their origin and the molecular networks that regulate neurogenesis and function are poorly understood. Here we studied human post-mortem hippocampi obtained from different cohorts: young adults with intact memory, aged adults with no cognitive impairments, aged adults with extraordinary memory capacity (SuperAgers)14,15, adults with preclinical intermediate pathology or adults with AD. Using multiomic single-cell sequencing (single-nucleus RNA sequencing and single-nuclei assay for transposase-accessible chromatin with sequencing), we analysed the profiles of 355,997 nuclei isolated from the hippocampus samples and identified neural stem cells, neuroblasts and immature granule neurons. Dysregulated neurogenesis was largely associated with changes in chromatin accessibility. Analyses of transcription factors and target gene signatures that distinguished each of the groups revealed early alterations in chromatin accessibility of neurogenic cells from individuals with preclinical AD, and such changes were even more evident in samples from individuals with AD. We identified a distinct profile of neurogenesis in SuperAgers that may reflect a 'resilience signature'. Finally, alterations in the profile of astrocytes and CA1 neurons govern cognitive function in the ageing hippocampus. Together, our study points to a multiomic molecular signature of the hippocampus that distinguishes cognitive resilience and deterioration with ageing.

Identifying the causal variants and mechanisms that drive complex traits and diseases remains a core problem in human genetics1-5. Most of these variants individually have weak effects6 and lie in non-coding gene-regulatory elements7-10, for which we lack a complete understanding of how single-nucleotide alterations modulate transcriptional processes to affect human phenotypes5,11-15. To address this problem, we measured the activity of 221,412 fine-mapped trait-associated variants using a massively parallel reporter assay16-20 in 5 diverse cell types. We show that this assay effectively discriminates between likely causal variants and controls, and identified 13,121 regulatory variants with high precision. Although the effects of these variants largely agree with orthogonal measures of function, only 69% of them can plausibly be explained by the disruption of a known transcription factor binding motif. We investigated the mechanisms of 136 variants using saturation mutagenesis and assigned affected transcription factors for 91% of variants without a clear canonical mechanism. Finally, we detected regulatory epistasis at 11% of tested regulatory variants in close proximity and identified multiple functional variants on the same haplotype at a small, but important, subset of trait-associated loci. Overall, our study provides a systematic functional characterization of likely causal common variants that underlie complex and molecular human traits, enabling new insights into the regulatory grammar underlying disease risk.

Atopic diseases associated with allergens, as well as allergic diseases, frequently arise early in life; however, the age-dependent mechanisms governing immune responses to allergens remain poorly understood1. Here we find that in early life, exposure to common allergens triggers a distinct bifurcated immune response, simultaneously triggering type 17 inflammation in the skin and initiating canonical T helper 2 sensitization in the lymph nodes. This early-life γδ type 17-mediated dermatitis primes the exaggerated allergic lung inflammation upon secondary allergen exposure. Mechanistically, we find dendritic cell (DC)-mediated type 17 activation directly in the skin without requiring migration to lymph nodes; we term this state 'peripheral immune inducer' (pii) DC. CD301b+ conventional type 2 DCs acquire allergen, adopt the pii-DC state, produce IL-23 and activate local γδ type 17 cells independently of lymph-node engagement. The pii-DC state is enabled by the immature hypothalamic-pituitary-adrenal axis and physiologically low systemic glucocorticoids characteristic of early life2,3; DC-specific deletion of the glucocorticoid receptor recapitulates the pii-DC phenotype. These findings define a developmental checkpoint, set by neuroendocrine maturation, that enables in situ DC activation and immune induction, thereby shaping age-dependent responses to allergens.

Electrolyte solvents for electrochemical devices have been dominated by oxygen (O)-based and nitrogen (N)-based ligands over the past decades1-5, for which the dipole-ion (Li+, Na+ and so on) interaction usually lays the foundations of ion dissociation and transport but frustrates the charge transfer process at the electrolyte-electrode interface6-9. Here, by synthesizing alkanes with monofluorinated structures, we show that fluorine (F)-based ligands with designed steric hindrance and Lewis basicity enable salt dissolution of more than 2 mol l-1. Among them, 1,3-difluoro-propane (DFP)-based Li-ion electrolyte is endowed with all merits for energy-dense and low-temperature batteries, including low viscosity (0.95 cp), high oxidation stability (>4.9 V) and ionic conductivity of 0.29 mS cm-1 at -70 °C. By incorporating F atoms in the first solvation shell, the weak F-Li+ coordination facilitates the Li plating/stripping process with Coulombic efficiency (CE) up to 99.7% and exchange current density one magnitude larger than O-Li+ coordination at -50 °C. The electrolytes further enable the operation of lithium-metal pouch cells under an electrolyte amount of less than 0.5 g Ah-1, achieving energy densities greater than 700 Wh kg-1 at room temperature and about 400 Wh kg-1 at -50 °C. The hydrofluorocarbon (HFC) electrolytes in this work provide a feasible approach to building electrochemical systems beyond traditional coordination chemistry.

Multicellularity evolved independently multiple times in eukaryotes1-4. Two distinct mechanisms underpin multicellularity5: clonality (serial cell division without sister-cell separation) and aggregation (whereby independent cells assemble into a multicellular entity). Clonal and aggregative multicellularity are traditionally considered to be mutually exclusive1,6-8, with rare exceptions9, and evolutionary hypotheses have addressed why multicellularity might diverge towards one or the other extreme3,4. Both animals and their sister group, the choanoflagellates, are currently known to acquire multicellularity only clonally4,10,11. Here we show that the choanoflagellate Choanoeca flexa12 forms motile and contractile cell monolayers (sheets) through multiple mechanisms-C. flexa sheets can form purely clonally, purely aggregatively or through a combination of both processes. We characterize the life history of C. flexa in its natural environment-ephemeral splash pools on the island of Curaçao-and show that C. flexa undergoes reversible transitions between unicellularity and multicellularity during evaporation-refilling cycles. Different splash pools house genetically distinct strains of C. flexa and kin recognition constrains aggregation between them. We show that clonal-aggregative multicellularity is a versatile strategy for the robust establishment of multicellularity in this variable and fast-fluctuating environment. Our findings challenge former generalizations about choanoflagellates and expand the option space of choanozoan multicellularity.

Coral reefs are marine biodiversity hotspots that provide a wide range of ecosystem services1. They are reservoirs of bioactive metabolites, many produced by microorganisms associated with reef invertebrate hosts2. However, for the keystone species of coral reefs-the reef-building corals-we still lack a systematic assessment of their microbially encoded biosynthetic potential and the molecular resources at stake due to the alarming decline in reef biodiversity. Here we analysed microbial genomes reconstructed from 820 reef-building coral samples of three representative coral genera collected at 99 reefs across 32 islands throughout the Pacific Ocean (Tara Pacific expedition)3. By contextualizing our analyses with the microbiomes of other reef species, we found that only 10% of the 4,224 microbial species and less than 1% of the 645 species exclusively identified in Tara Pacific samples had genomic information available. Furthermore, the biosynthetic potential of reef-building coral microbiomes rivalled or surpassed that of traditional natural product sources such as sponges. Among the biosynthetically rich bacteria in the reef microbiome, we identified new groups of Acidobacteriota that encode previously unknown enzymology, in turn opening promising avenues for functional protein engineering. Together, this study underscores the importance of conserving coral reefs as vital reservoirs of molecular diversity.

Alvarezsauroids are an enigmatic clade of predominantly small-bodied theropod dinosaurs that are known mainly from the Jurassic to Cretaceous periods of Asia and South America1-3. Late Cretaceous alvarezsauroids possess specialized forelimbs adapted for digging4,5, minute supernumerary teeth and heightened sensory capacities6, and are interpreted as myrmecophagous. They are hypothesized to exhibit evolutionary miniaturization coupled to their dietary specialization2. Fragmentary South American taxa are traditionally arrayed as a paraphyletic grade with respect to the Late Cretaceous Asian subclade Parvicursorinae2,3, invoking dispersal to explain their disjunct distributions. Here we describe a skeleton of the alvarezsauroid Alnashetri cerropoliciensis7 representing to our knowledge the most complete and smallest South American taxon to date. We also recognize two alvarezsauroids among historic taxa from the Northern Hemisphere. Phylogenetic analysis recovers Alnashetri among basal non-alvarezsaurids, rendering South American taxa polyphyletic. Combined with the new taxa recognized here, our biogeographical analyses infer a Pangaean ancestral distribution for Alvarezsauroidea, with vicariance dominating the early history of the clade. The early branching position of Alnashetri among larger-bodied relatives revises best-fit models of body size evolution in alvarezsauroids-we find no support for evolutionary miniaturization but, rather, find support for repeated evolution within a narrow body size range.

Orchestration of lipid production, storage and mobilization is vital for cellular and systemic homeostasis1,2. Dysfunctional plasma lipid control represents the major risk factor for cardiometabolic diseases-the leading cause of human mortality3,4. Within the cellular landscape, the endoplasmic reticulum (ER) is the central hub of lipid synthesis and secretion, particularly in metabolically active hepatocytes in the liver or enterocytes in the gut5,6. Initially assembled in the ER lumen, lipid-ferrying lipoproteins necessitate the cross-membrane transfer of both neutral and phospholipids onto the lumenal apolipoprotein B (APOB), in a poorly defined process7-10. Here we show that the ER protein CLCC1 regulates cellular lipid partition and, consequently, systemic lipid homeostasis by participating in trans-bilayer equilibration of phospholipids. CLCC1 partners with the phospholipid scramblase TMEM41B11,12 to recognize imbalanced bilayers and promote lipid scrambling, thereby supporting lipoprotein biogenesis and the subsequent bulk lipid transport. Loss of CLCC1 or TMEM41B leads to the emergence of giant lumenal lipid droplets enclosed by imbalanced ER bilayers and, consequently, accelerated pathogenesis of metabolic-dysfunction-associated liver steatohepatitis. The results reveal that phospholipid scrambling at the ER is essential for establishing a dynamic equilibrium. Considering the requirement of trans-bilayer phospholipid equilibration in numerous biological processes, ranging from catabolic autophagy to viral infection13-16, we anticipate that future work will elucidate a homeostatic control mechanism intrinsic to ER function in lipid biogenesis and distribution.

Chimeric antigen receptor (CAR)-natural killer (NK) cell therapies hold promise for solid tumours but remain limited because of poor tumour infiltration, persistence and resistance in the tumour microenvironment1-4. Here, to identify gain-of-function targets that enhance CAR-NK cell efficacy, we performed an unbiased in vivo CRISPR activation screen followed by a barcoded targeted in vivo open reading frame screen in primary human CAR-NK cells. We identified and comprehensively validated OR7A10, a G protein-coupled receptor (GPCR), as the top candidate. Engineering CAR-NK cells with OR7A10 cDNA (a CRISPR-independent method with a simple manufacturing strategy) enhanced their proliferation, activation, degranulation, cytokine production, death ligand expression, chemokine receptor expression, cytotoxicity, persistence, metabolic fitness and tumour microenvironment resistance. Moreover, exhaustion in primary human NK cells derived from multiple peripheral blood and cord blood donors was reduced. OR7A10 gain-of-function CAR-NK cells displayed strong in vivo efficacy across multiple solid tumour models. For example, 100% complete response with long-term tumour control and survival benefit in an orthotopic breast cancer mouse model were achieved. These findings establish OR7A10-engineered CAR-NK cells as a highly potent and scalable off-the-shelf therapeutic for solid tumours.

Chiral antiferromagnets1,2 host octupole order3,4 and combine the advantages of antiferromagnets and ferromagnets. Despite the development of numerous switching strategies5-9, the field-free full switching remains unknown, posing an important obstacle to their practical application in memory technology. Here we prepared a homo-junction constituted of Mn3Sn(0001) bottom layer and polycrystalline Mn3Sn top layer. The tilted Kagomé geometry in polycrystalline Mn3Sn divides the out-of-plane spin polarization from Mn3Sn(0001) layer10,11 into the out-of-Kagomé-plane and in-Kagomé-plane components, generating the symmetric (antiferromagnet-type) and asymmetric (ferromagnet-type) driving forces, respectively. The former accelerates octupole rotation, whereas the latter determines switching chirality. Field-free full switching is realized in the unconventional protocol that integrates the advantages of both antiferromagnetic and ferromagnetic switching. It goes beyond the conventional full-switching framework requiring perpendicular uniaxial anisotropy7,12. An unprecedented switching efficiency is achieved, with both current density and power consumption an order of magnitude lower than in previous configurations, by virtue of the highly efficient driving forces due to spin-torque characteristics of octupole order and the ultralow energy barrier arising from easy-plane anisotropy, overcoming their trade-off in conventional protocols. The zero-field switching also shows the advantages of octupole-programmable chirality and robustness to external magnetic field.

Antimicrobial drug resistance poses a global health challenge that necessitates the identification of new druggable targets1-3. The essential lipid II flippase MurJ is a promising yet underexplored antimicrobial target in bacterial cell wall biosynthesis4-7. The only known inhibitors of Gram-negative (diderm) MurJ are the single-gene lysis proteins (Sgls) from the lytic single-strand RNA phages M (SglM) and PP7 (SglPP7)8,9. SglM and SglPP7 have distinct evolutionary origins and share no sequence similarity. Here we describe a common mechanism of MurJ inhibition by these phage-encoded Sgls. We determined the structures of MurJ-bound SglM and SglPP7 and discovered a third distinct MurJ-targeting Sgl from the predicted phage Changjiang3 (SglCJ3) that we also characterized structurally. Our findings demonstrate that all three Sgls evolved convergently to trap MurJ in a periplasm-open conformation through a common MurJ interface, revealing a pathway for drug design.

Cold stress restricts plant growth and inorganic phosphate (Pi) uptake, reducing yield and increasing fertilizer demand1-3. Enhancing both cold tolerance and phosphorus use efficiency (PUE) is crucial for sustainable crop productivity. Here we identify the SPX-domain-containing E3 ubiquitin ligase NITROGEN LIMITATION ADAPTATION (NLA) as a central regulator that links cold signalling to Pi homeostasis in maize (Zea mays L.). Under cold conditions, NLA promotes the degradation of the transcriptional repressor JAZ11, activating jasmonate signalling to enhance cold tolerance; however, NLA also simultaneously represses Pi uptake, through inositol polyphosphate (InsP)-dependent ubiquitination of the Pi transporter PT4. A ubiquitinome-informed genome-wide association study identified a natural PT4(K267A) (lysine-to-alanine substitution) variant that attenuates NLA-mediated degradation and increases Pi uptake in cold conditions. To overcome this nutrient-stress trade-off, we combined artificial-intelligence-guided structural modelling and ligand docking with genome editing to generate the nlaΔ12 allele, which encodes an NLA variant in which binding to InsP is impaired but JAZ11 targeting is retained. The Δ12 modification selectively redirects the activity of NLA towards jasmonate signalling, resulting in improved cold resilience, higher PUE and increased yield in multi-site field trials. These findings reveal a tunable SPX regulatory module that integrates environmental and nutrient signals, and provide a molecular framework for engineering climate-resilient, nutrient-efficient crops.

Cellular solids ubiquitously exist in natural systems and are crucial for living organisms1,2. Their unique smooth branch and node morphologies are often seen as adaptations for enhanced mechanical performance3,4. Exploring alternative evolutionary functions can enrich the understanding of cellular solids, but it is frequently neglected. Here we show that the biomineralized cellular solids in echinoderm stereom (for example, sea urchin spine) have unexpected mechanoelectrical perception with response potential and response time, both of which are one to three orders of magnitude greater than those of echinoderm vision5. This exceptional perception originates from the gradient cellular solids (with varying void- or solid-phase diameters) along the [001] spine axis, generating a differential charge density across the stereom surface during liquid flow. Inspired by this natural wisdom, we create artificial spine-like structures using three-dimensional printing technology that exhibit three-fold higher voltage output and eight-fold greater amplitude differential than gradient-free samples, as well as a nature-inspired metamaterial mechanoreceptor capable of time-resolved self-monitoring information underwater. Our findings advance the understanding of load-sensitive biomimetic cellular solids (such as wood, sponge and trabecular bone), with the potential to develop functional gradient cellular materials towards underwater spatiotemporal sensing and water resource utilization.

Imbalances in lipid storage and secretion lead to hepatic steatosis, the accumulation of lipid droplets in hepatocytes1,2. Our understanding of the mechanisms that govern the channelling of neutral lipids in hepatocytes towards cytosolic lipid droplets or secreted lipoproteins remains incomplete3,4. Here we performed a series of CRISPR-Cas9 screens under different metabolic states that led to the identification of CLCC1 as a critical regulator of neutral lipid storage and secretion in hepatocytes. Loss of CLCC1 resulted in the buildup of large lipid droplets in hepatoma cells and Clcc1 knockout in mice caused liver steatosis. Lipid droplets were present in the lumen of the endoplasmic reticulum of the Clcc1-knockout hepatocytes and exhibited properties of lipoproteins, indicating a profound shift in neutral lipid flux. The loss of CLCC1 also led to the accumulation of nuclear membrane herniations accompanied by a reduction in nuclear pores. Remote homology searches identified a domain in CLCC1 that is homologous to yeast Brl1 and Brr6, factors that promote nuclear envelope fusion during nuclear pore complex assembly. Molecular dynamics simulations and mutagenesis studies support a model in which CLCC1 mediates membrane bending and fusion. We propose that CLCC1 mediates membrane fusion to promote hepatic neutral lipid flux and nuclear pore complex assembly.