Efficient and precise delivery of therapeutics toward target loci of organs is crucial for effective disease therapy. However, conventional devices face remarkable challenges to achieve clinically desirable conformality, spatial controllability, and efficiency, especially to organs with complex anatomies, due to a lack of appropriate mechanical and/or material properties. Here, we report a bioelectronic patch for organ-conformal, kirigami-structured electro-transfection (POCKET) that features high conformality enabled by parametric customization, achieving a theoretically maximum effective coverage area over the target organ. The four-layered POCKET forms a unique nanopore-cell juxtaposition configuration at the tissue-device interface, which induces precise, uniform electro-perforation while expediting intracellular transport of payloads. The high delivery efficiency and precise spatial controllability have been systematically validated with various organs. POCKET-mediated therapeutic delivery achieved organ protection from accumulated DNA damage or ischemia-reperfusion injury, restoring organ functionalities. This work presents a customizable technique with translational value for precise therapy in challenging target organs.

Approximately one-third of clinical drugs mediate their therapeutic effects through G protein-coupled receptors (GPCRs), highlighting their immense therapeutic relevance. Novel approaches to modulate GPCR activity have the potential to yield unique pharmacological profiles. Conventionally, the G protein and β-arrestin signaling pathways downstream of GPCRs have been viewed as mutually exclusive. Using the in-house developed survival pressure selection (SPS) method, a high-throughput platform for GPCR agonist discovery, we identified an allosteric ligand that stabilizes a GPCR-G protein-β-arrestin megacomplex, thereby mediating sustained receptor signaling following internalization. Remarkably, this compound, atazanavir, exhibits pan-receptor activation across multiple family A GPCRs, including GPR119, β1AR, and β2AR, demonstrating the broad applicability of this regulatory mechanism. This discovery uncovers a distinct mechanism of GPCR regulation, opening alternative avenues for the development of therapeutics targeting GPCRs.

Higher organisms spread external stimuli from the perceptive tissues to the whole body to achieve systemic responses. In plants, guard cells sense pathogens and close stomata to prevent their entry. We observed that pathogen-infected local leaves transmit the danger status to uninfected distal systemic leaves and trigger their stomatal closure as a global defense termed systemic stomatal immunity (SSIM). The underlying mobile signals remain unknown. Here, we report that an upstream open reading frame (uORF)-encoded systemic stomatal immune conductor (USIC) acts as a long-distance mobile peptide inducing SSIM. In local leaves, USIC increases upon pathogen/pattern signals and is secreted into the apoplast for long-distance transport. In systemic leaves, USIC is perceived by the cell surface SUCROSE-INDUCED RECEPTOR KINASE 1 (SIRK1)-KINASE 7 (KIN7) receptor complex and induces METACASPASE 4 (MC4)-mediated KIN7 cleavage. KIN7 associates with proton pumps/aquaporins to regulate stomatal closure. This study reveals a systemic signaling mechanism whereby an uORF-encoded mobile signal and its receptor pathway activate SSIM.

The emergence and sustained spread of H5N1 in US dairy cattle since 2024 have demonstrated that highly pathogenic avian influenza (HPAI) is capable of establishing long-term transmission in livestock. Genomic surveillance has clarified national patterns of spatial diffusion, interspecies transmission, and viral evolution, but critical data gaps remain that impede efforts to track virus movements in real time, identify modes of transmission, and inform control efforts.

The 2018-2020 Ebola virus disease (EVD) epidemic facilitated the emergence of viral mutations, enhancing the potential for host adaptation during sustained human transmission. Here, we identified the Ebola virus (EBOV) glycoprotein V75A (GP-V75A) substitution as a dominant variant during the epidemic. This substitution, located within the receptor-binding domain, emerged early in the outbreak and rapidly reached high prevalence. GP-V75A demonstrated enhanced infectivity in multiple cell lines and murine models. Mechanistically, GP-V75A increased viral GP binding affinity to the host receptor Niemann-Pick C1 (NPC1) and reduced the dependency on endosomal cysteine proteases for entry. Notably, GP-V75A also significantly reduced the efficacy of NPC1-targeting compounds and neutralizing antibodies. Epidemiological analysis indicated that the rise in GP-V75A prevalence coincided with the increase in case number during the outbreak. These findings provide crucial insights into the evolutionary adaptation of EBOV during large-scale outbreaks and underscore the importance of real-time genomic surveillance for improving epidemic preparedness.

Alzheimer's disease (AD) and cancer are among the most devastating diseases worldwide. Epidemiological data indicate that the incidence of AD significantly decreases in patients with a history of cancer. However, whether and how peripheral cancer may affect AD progression is yet to be studied. Here, we find that peripheral cancer inhibits amyloid pathology and rescues cognition via secretion of cystatin-c (Cyst-C), which binds amyloid oligomers and activates triggering receptor expressed on myeloid cells 2 (TREM2) in microglia, enabling microglia to degrade the pre-existing amyloid plaques in AD mice. These effects of Cyst-C are abolished by a cell-type-specific deletion (Cx3cr1TREM2-/-) or mutation of TREM2 (TREM2R47H) or Cyst-C (Cyst-CL68Q) in microglia. Together, these findings provide significant conceptual advances into cancer neuroscience and establish therapeutic avenues that are distinct from the present amyloid-lowering strategies, aiming at degrading the existing amyloid plaques for precision-targeted AD therapy.

In response to perturbed transcription elongation, the MYC oncoprotein multimerizes and undergoes a phase transition. Here, we demonstrate that MYC globally relocalizes from its canonical positions on DNA to nascent RNA upon accumulation of intronic RNA. Upon binding to RNA, MYC forms multimers that concentrate the nuclear exosome, an RNA exonuclease, and its targeting complexes around double-stranded RNA and R-loops. MYC harbors four RNA-binding regions (RBRI-IV). RBRIII promotes MYC multimerization and is necessary for recruiting the exosome to R-loops. RBRIII is dispensable for transcriptional activation and pancreatic tumor cell proliferation in culture, but it is indispensable for sustaining tumor growth in vivo. Via RBRIII, MYC suppresses the accumulation of R-loop-derived RNA-DNA hybrids and prevents them from activating the innate immune kinase TBK1 via the TLR3 pattern recognition receptor. Our data demonstrate that the phase transition of MYC is an RNA-driven stress response that suppresses the accumulation of immunogenic RNA-DNA hybrids.

Mutations in lysosomal genes cause neurodegeneration and neuronopathic lysosomal storage disorders (LSDs). Despite their essential role in brain homeostasis, the cell-type-specific composition and function of lysosomes remain poorly understood. Here, we report a quantitative protein atlas of lysosomes from mouse neurons, astrocytes, oligodendrocytes, and microglia. We identify dozens of proteins not previously annotated as lysosomal and reveal the diversity of lysosomal composition across brain cell types. Notably, we identified SLC45A1, a gene whose mutations cause a monogenic neurological disease, as a neuron-specific lysosomal protein. Loss of SLC45A1 causes lysosomal dysfunction in vitro and in vivo. SLC45A1 functions as a lysosomal sugar transporter and impacts the stability of the V1 subunits of the vacuolar ATPase (V-ATPase). Consistently, SLC45A1 loss reduces lysosomal V1 subunits, elevates lysosomal pH, and disrupts iron homeostasis, causing mitochondrial dysfunction. Altogether, our work redefines SLC45A1-associated disease as an LSD and establishes a comprehensive map to study lysosome biology at cell-type resolution.

Progress toward anti-scarring therapies has been hampered by our limited understanding of fibroblast populations underlying fibrotic vs. regenerative healing. The site-dependent fibroblast heterogeneity acquired during development points to cell-intrinsic properties determining fibroblasts' scarring potential. Using a mouse wounding model, we observed that facial wounds heal with less scarring than scalp, ventral, and dorsal wounds. Single-cell RNA sequencing identified increased expression of Robo2 and downstream Eid1 in neural-crest-derived facial fibroblasts compared with fibroblasts from other sites. In fibroblast transplantation experiments, Robo2 and Eid1 promoted facial fibroblasts' reduced fibrotic potential. This is maintained by the inhibition of EP300 histone acetyltransferase, leading to a more transcriptionally silent chromatin landscape. Mimicking EID1's activity, small-molecule and transgenic EP300 repression in dorsal wounds promoted facial-like healing with reduced scarring. These data highlight the importance of ROBO2-EID1-EP300 signaling in facial wound healing and demonstrate our ability to modulate fibroblasts' embryologically determined fibrogenic potential to minimize scarring.

Cellular senescence and brain atrophy are both associated with brain aging, suggesting these processes may share underlying biological mechanisms. This study investigated these mechanisms by integrating structural neuroimaging with gene and protein expression data from prefrontal cortex tissue collected from individuals who underwent neurosurgery. Cell-type-specific gene expression signatures associated with neuroimaging features and cellular senescence were identified and replicated in several independent datasets. Significant correlations between these signatures were observed in excitatory neurons and microglia, especially for volume-related features. These associations were also observed for excitatory neurons in an independent brain gene expression dataset from individuals below 5 years of age, implying a role for senescence during brain development. Together, this study provides a deep characterization of molecular signatures linking brain structure and cellular senescence across different life stages and suggests mechanisms supporting brain development may also contribute to volume reduction observed during aging.

The ability to design and engineer mammalian genomes across arbitrary length scales would transform biology and medicine. Such capabilities would enable the systematic dissection of mechanisms governing gene regulation and the influence of complex haplotypes on human traits and disease. They would also facilitate the engineering of disease models that more faithfully recapitulate human physiology and of next-generation cell therapies harboring sophisticated genetic circuits. Over the past decade, advances in genome editing have made small, targeted modifications at single sites routine. However, achieving multiple coordinated alterations across long sequence windows (>10 kb) or installing large synthetic DNA segments in mammalian cells remains a major challenge. Recent advances in mammalian genome writing-the bottom-up design, assembly, and targeted integration of large custom DNA sequences, independent of any natural template-offer a potential solution. Here, we review key technological developments, highlight emerging applications, and discuss current bottlenecks and strategies for overcoming them.

Human stem-cell-based embryo models (SCBEMs) imperfectly mimic some-but not all-features of early human development. Yet as these models become increasingly sophisticated, they raise important ethical and regulatory questions. Despite their limitations, SCBEMs already offer powerful platforms to study human embryology, infertility, reproduction, and regenerative medicine. To avoid restrictions that could stall progress for decades, it is essential to proactively establish a clear regulatory framework-one that protects public trust without inhibiting scientific progress. We propose a two-tiered oversight structure anchored in a single fixed ethical principle: no SCBEM should ever attain the capacity for sentience (the ability to experience sensory inputs, such as pain). Tier 1 sets a developmental limit at two criteria: neural tube closure or the appearance of both a defined number of somites and limb buds, corresponding to ∼Day 28 post-fertilization analogue (PFA). Tier 2 allows research requiring a higher level of oversight up to Day 56 PFA, remaining well before the earliest debated threshold of sentience. This framework provides proportionate oversight and enforceable boundaries while acknowledging that concerns beyond sentience will persist for some stakeholders. Our goal is to prepare responsibly for the future, when the models become improved, enabling discovery without compromising ethical integrity.

In the current issue of Cell, three papers describe new mechanistic information about how EBV transforms B cells to become antigen-presenting cells in the brain that drive demyelinating disease.1,2,3.

Multiplex immunofluorescence proteomics is a powerful method in spatial biology to decipher cell types, states, and architecture in tissues. In this issue of Cell, Valanarasu et al. develop GigaTIME, an expansive population-scale analysis of the tumor immune microenvironment of over 14,000 patients across 24 cancer types, enabling clinical discovery and patient stratification.

Olfactory receptors (ORs) are a diverse superfamily of G protein-coupled receptors responsible for odor detection that are also implicated in non-olfactory physiological functions. OR6A2, a class II OR, selectively senses medium-chain aldehydes and belongs to a cluster of ORs genetically associated with the "soapy" perception of cilantro. It also modulates macrophage-mediated inflammatory responses. Structural studies of ORs have long been challenging. Using a back-mutation strategy, we engineered a functional OR6A2 variant (bmOR6A2) from a consensus OR6 (consOR6). Structures of bmOR6A2 in complex with aldehydes reveal a novel ligand-recognition mechanism involving a reversible Schiff base linkage with residue K4.60, validated by mass spectrometry. By integrating structures of consOR6, molecular dynamics simulations, and functional assays, we identified a conserved D45.51Y6.55Y7.41 triad critical for activation in class II ORs. These findings establish a practical strategy for decoding odorant recognition, offering new insights into olfaction signaling and applications in fragrance and therapeutic development.

Smell is one of the fundamental senses mediated by thousands of odorant receptors (ORs). How hydrophobic and volatile odor molecules are recognized by class II ORs remains elusive. Here, we present cryo-electron microscopy (cryo-EM) structures of class II OR Olfr110 complexed with the unsaturated fatty acid metabolite (UFAM) PL45, Gs, and cons-OR5. The structural study revealed an unusually large hydrophobic pocket accommodating PL45 and the endogenous agonist 12(S)-hydroxyeicosapentaenoic acid (12(S)-HEPE). This pocket is decorated with polar residues and aromatic residue arrays, constituting polar networks and π-π interactions with the natural agonist PL45, respectively. Conserved motifs in the type II OR5 subfamily responsible for ligand recognition are characterized. The inward movement of extracellular loop 3 (ECL3) and an unconventional activation mechanism underlie Olfr110 activation. At the G protein interface, Olfr110 displays common and unique interactions. Overall, we revealed the structural basis of odor recognition and the activation mechanism of class II ORs, which may facilitate drug development targeting these receptors.

Oxylipins are important metabolic messengers for normal life activities, and olfactory receptors (ORs) are known for their low affinity for odor and are not considered oxylipin receptors. By developing the "anonymous receptor identification by reverse-G-protein pull-down" (ARIG) method, we identify orphan OR Or5v1/Olfr110 as an oxylipin 12(S)-hydroxyeicosapentaenoic acid (12(S)-HEPE) receptor. The serum from obese patients with increased BMI showed lower Or5v1/Olfr110-Gs activation compared with normal people. Systemic Or5v1/Olfr110 deficiency or liver-specific Or5v1/Olfr110 deficiency impaired glucose homeostasis, even after stimulation with 12(S)-HEPE. Engagement of 12(S)-HEPE with Olfr110 activated Gs-PKA-pATF2-Cpt1α signaling to reduce obesity through promotion of fatty acid oxidation in liver. Structural aided development of synthetic agonist HOR1-C59 improved glucose homeostasis, which is dependent on Or5v1/Olfr110 expression. Overall, we revealed that a high-affinity oxylipin-sensing OR plays key roles in metabolism. The beneficial effects of HOR1-C59 underscore the therapeutic value of small synthetic compounds that target ORs for disease treatment.

Human genetic association studies highlight key genes involved in disease pathology, yet targets identified by these analyses often fall outside the traditional definitions of druggability. A rare truncated variant of the scaffold protein CARD9 is linked with protection from Crohn's disease, prompting us to pursue the development of inhibitors that might similarly modulate innate inflammatory responses. Using a phased approach, we first identified a ligandable site on CARD9 using a structurally diverse DNA-encoded library and defined this site in detail through X-ray crystallography. Building upon this, a subsequent ligand displacement screen identified additional molecules that uniquely engage CARD9 and prevent its assembly into scaffolds needed to nucleate a signalosome for downstream nuclear factor κB (NF-κB) induction. These inhibitors suppressed inflammatory cytokine production in dendritic cells and a humanized CARD9 mouse model. Collectively, this study illustrates a strategy for leveraging protective human genetic variants and chemical biology to tackle challenging targets for dampening inflammation.

Essential for eukaryotes, multiple copies of the exocyst complex tether each secretory vesicle to the plasma membrane (PM) in constitutive exocytosis. The exocyst higher-order structure (ExHOS) that coordinates the action of these multiple exocysts remains unexplored. We integrated particle tracking, super-resolution microscopy, and cryo-electron tomography to time-resolve the continuum conformational landscape of the ExHOS and to functionally annotate its different conformations. We found that 7 exocysts form a flexible ring-shaped ExHOS that tethers vesicles at <45 nm from the PM. The ExHOS rapidly expands while pulling the vesicle toward the PM in a stepwise mechanism comprising three metastable states at 27, 18, and 5 nm from the PM. After fusion, Sec18 mediates the disassembly of the stationary ExHOS, a function that controls the rate of exocytosis. By resolving biophysical principles in situ, we reconstructed the spatiotemporal dynamics of the multimeric architecture controlling vesicle tethering in exocytosis.