Decoupled antigen binding and CD3 signalling in allogeneic T cells

This issue highlights the engineering of T cells and other immunomodulatory therapeutic cells with augmented functionality, for use to treat HIV, cancers, red-blood-cell disorders and injured, inflamed tissue.

The cover illustrates that allogeneic T cells can be engineered with a T cell receptor that decouples antigen-mediated T cell activation from T cell cytotoxicity.

See Kapetanovic et al.

Biomolecular condensates as intracellular drug reservoirs

This issue highlights histopathological biomarkers for predicting the tumour accumulation of nanomedicines, the profiling of protein–protein interactions to predict the efficacy of inhibitors of acute myeloid leukaemia, the intravenous injection of oxygen via polymeric microbubbles for the treatment of hypoxaemia, the structural optimization of ionizable lipids in nanoparticles to improve their delivery activity and biodegradability, the radiation-induced reduction of platinum prodrugs, exosome-loaded degradable polymeric microcapsules for the treatment of vitreoretinal diseases, antibody-displaying extracellular vesicles for cancer therapy, the controlled formation of biomolecular condensates as intracellular drug reservoirs, and how amine headgroups in ionizable lipids drive the immunogenicity of lipid nanoparticles.

The cover illustrates a method for forming biomolecular condensates that serve as drug reservoirs within cancer cells.

See Liang et al.

An immunosuppressive subcutaneous niche for treating ulcerative colitis

This issue highlights an injectable zwitterionic gel that can be applied to the tip of insulin-infusion catheters, week-long normoglycaemia in diabetic mice and minipigs via glucose-responsive insulin, subcutaneous biodegradable scaffolds for restimulating the antitumour activity of pre-administered CAR T cells, an injectable subcutaneous colon-specific immune niche for the treatment of ulcerative colitis, subcutaneous neovascularization for the long-term survival of encapsulated islets without immunosuppression, prevention of peri-implant fibrosis by functionally inhibiting skeletal cells expressing the leptin receptor, and the discovery of immunometabolic cues reprogramming the microenvironment around implanted biomaterials.

The cover illustrates an injectable subcutaneous colon-specific niche consisting of colon epithelial cells, decellularized colon extracellular matrix and immunosuppressive nanofibres.

See Au et al.

Bacteria and neutrophil extracellular traps drive dental calculi

This issue highlights a near-infrared dye for fluorescence-guided tumour resection and the assessment of wound healing, an inexpensive light-sheet fluorescence microscope for the high-resolution imaging of cleared and living samples at scale, transient pacing in pigs with complete heart block via myocardial injection of mRNA coding for a transcription factor, an analysis of neuroimaging data across mental health, neurodegenerative, psychiatric and neurodevelopmental diagnostic categories, that blocking the mechanical sensor PIEZO1 in cytotoxic T lymphocytes augments their cytotoxicity against tumour cells, and that bacteria-mediated resistance of neutrophil extracellular traps to enzymatic degradation drives the formation of dental calculi.

The cover illustrates that the development of dental calculi involves bacteria in local mature biofilms converting the DNA in neutrophil extracellular traps from being degradable by the enzyme DNase I to being degradation-resistant.

See Wan et al.

Softening intravenous insertion

This issue highlights an intravenous needle that softens on insertion, a bilingual speech neuroprosthesis, spinal-cord stimulation for the restoration of sensory feedback in individuals with transtibial amputation, a thermoelectric device for the restoration of thermal perceptions in a phantom hand, nanowire arrays for restoring vision, implantable temperature sensors for monitoring intestinal inflammation, and the recapitulation of neuropathogenesis induced by SARS-CoV-2 in a lung–brain microphysiological system.

The cover illustrates an intravenous needle whose stiffness and shape depend on body temperature so that it can soften on insertion.

See Agno et al.

Seeking antibiotics in the proteomes of extinct organisms

This issue highlights methods for spatial multi-omics at subcellular resolution, for the mapping of higher-order protein interactions, for studying the functions of non-coding regulatory elements, for interrogating sequence variation in antimicrobial peptides, for antimicrobial-peptide discovery by mining the proteome of extinct organisms, for reinforcing the intestinal mucosal barrier, and for the optogenetic stimulation of vagal nerves, to enhance glucose-stimulated insulin secretion.

The cover illustrates that compounds with antibiotic properties can be discovered by mining, using deep learning, the proteomes of all available extinct organisms.

See Wan et al.

Microscopic localization of fluorescence during glioma-resection surgery

The cover illustrates that paired stimulated Raman histology and two-photon excitation fluorescence microscopy improves the detection of fluorescent protoporphyrin IX during glioma-resection surgery.

See Nasir-Moin et al.

Supramolecular bispecific T cell engagers with controllable disassembly

This issue highlights advances in the design of bispecific T cell engagers, chimeric antigen receptor T cells, mineralized bacteria and other cellular as well as molecular immunotherapies for the modulation of the activity of the immune system against cancers and other inflammatory conditions.

The cover illustrates the small-molecule-mediated control of the antitumour activity of a supramolecular bispecific T cell engager through its disassembly.

See Gong et al.

Engineering extracellular vesicles to target T cells

This issue highlights intestinal organoids for the analysis of off-tumour toxicities of T-cell-engaging bispecific antibodies, the affinity maturation of mouse B cells reprogrammed to express human antibodies, modular chimaeric cytokine receptors with leucine zippers, engineered extracellular vesicles for targeting T cells and for the delivery of mRNA to neurons, immune-privileged tissues formed from immunologically cloaked mouse embryonic stem cells, mesenchymal stromal cells with chimaeric antigen receptors, the generation of antigen-specific mature T cells from engineered stem cells, and engineered heart tissue for the study of metabolic rewiring during tachycardia.

The cover illustrates that extracellular vesicles can be engineered with multiple functionalities for the targeted delivery of biologics to T cells.

See Stranford et al.

Multi-pass flow cytometry via laser-light barcodes

This issue highlights a high-throughput method for the rapid discovery of high-affinity antibodies, the large-scale mass-spectrometric quantification of glycopeptides in plasma, an assay for the identification, sorting and profiling of killer cells, high-throughput microfluidics for the identification of druggable regulators of cell secretion, the prediction of interactions between drugs and intestinal drug transporters, the high-throughput identification of genetic and cellular drivers of syncytium formation induced by SARS-CoV-2, multi-pass flow cytometry for measuring single-cell dynamics, and an assay for sensing the DNA-mismatch tolerance of Cas9.

The cover illustrates that barcoding cells with microparticles that emit near-infrared laser light allows for multi-pass flow cytometry with more markers and fewer colours.

See Kwok et al.

Stable transposon-driven integration of transgenes into immune cells

This issue highlights optimized base editors targeting the exon-7 mutation in SMN2 to restore the expression of the survival motor neuron protein to normal levels, the virus-mediated delivery of a transposon and an mRNA-encoded transposase for the integration of transgenes into immune cells, the enhanced viability of genome-engineered T cells transfected by electroporation via an isotonic buffer that dampens cytosolic cGAS–DNA interactions, the annotation of variants of the BRCA2 gene in human pluripotent stem cells, that host genes involved in viral processes can constrain the lentiviral delivery and expression of Cas13, and that replacing amino acid residues in an immunodominant and conserved T cell epitope in the capsid of an adeno-associated virus can abrogate its immunogenicity while preserving its function and potency.

The cover illustrates a gene-delivery system that enhances the stability of the integration of a desired transgene in immune cells by relying on a Sleeping Beauty transposase encoded into an mRNA delivered by an adeno-associated virus.

See Ye et al.

Modelling latent structures in neural activity to better predict behaviour

This issue highlights computational methods for use in multi-omics microsampling to profile lifestyle-associated changes, for the design of humanized versions of antibodies with improved stability, for the optimization of monoclonal antibodies for reduced self-association and non-specific binding, for the classification of tumour type and the prediction of microsatellite status on the basis of somatic mutations, for describing macroscopic resting-state brain dynamics, and for modelling nonlinear latent factors and structures in the activity of neural populations to enable flexible inference.

The cover illustrates that latent factors and latent structures in the activity of neural populations can be computationally modelled to better predict neural activity and behaviour.

See Abbaspourazad et al.