Nuclear mechanosensing and chromatin reorganization in cardiac cells

This issue highlights findings on disease-relevant cellular mechanosensing, including that T-cell-mediated cancer-cell killing is hampered for cortically soft cancer cells, that growing metastatic lesions in lymph nodes generate compressive stresses that impair T-cell entry, that the stiffness of the surface of silicone breast implants contributes to their fibrotic encapsulation, that the ion channel PIEZO1 senses shear stresses in tenocytes, how the viscoelasticity of the matrix affects osteoarthritic chondrocytes, that nuclear mechanosensing drives chromatin remodelling in persistently activated fibroblasts, and how nuclear deformation guides chromatin reorganization in cardiac disease.

The cover illustrates that, in cardiomyocytes under contraction, epigenetically marked chromatin preferentially accumulates in the periphery of the cell’s nucleus.

See Article Seelbinder et al.

Intratumoural activation of CAR T cells via focused ultrasound

This issue highlights the engineering of T cells to infiltrate pancreatic tumours, a bispecfic antibody for the rejuvenation of tumour-specific T cells, checkpoint-blockade antibodies conjugated to glucosylated polymers for glioblastoma therapy, the site-specific PEGylation of IL-2, an antibody for the concurrent depletion of tumour cells and immunosuppressive cells, an organoid-based screen for epigenetic inhibitors that stimulate antigen presentation, the control of the activity of CAR T cells via local elevations in temperature, the direct reprogramming of natural killer cells, an orally administered gel generating systemic antitumour immunity, and nanobody–antigen adducts for the induction of antigen-specific tolerance.

The cover illustrates that T cells can be engineered to express a chimaeric antigen receptor within tumours when heat is locally generated by pulses of focused ultrasound.

See Wu et al.

Wireless monitoring of deep wounds via bioelectronic sutures

This issue highlights that the surface topography of silicone breast implants mediates the foreign-body response to them, a paste for rapid haemostatic sealing, coagulation-factor-adsorbing hydrogel microspheres for extracorporeal blood purification, cardiac patches for repairing infarcted myocardium, exosome-eluting stents for vascular healing, lubricating polymers for cartilage regeneration, the prevention of vascular-allograft rejection via immunosuppresive polymers, bioelectronic surgical sutures for the monitoring of deep wounds, and single-cell transcriptomics to reconstruct signalling networks surrounding implanted biomaterials.

The cover illustrates surgical sutures incorporating wirelessly operated pledgets for the monitoring of deep surgical sites.

See Kalidasan et al.

Prolonged local anaesthesia via nanofibres mimicking interactions on a sodium channel

This issue highlights drug-delivery strategies and technologies, from nanoscale delivery systems to implantable biomaterial drug depots to microneedle arrays, for a number of biomedical applications in ophthalmology, oncology, endocrinology, immunology, rheumatology, anaesthesiology and treating infectious diseases.

The cover illustrates that self-assembled nanofibres carrying site-1 sodium channel blockers and designed to mimic specific interactions of the blockers with peptide sequences on voltage-gated sodium channels led to prolonged nerve blockade with low systemic toxicity in rats.

SeeArticle Ji et al.

A microphysiological model of fungal infection of the brain

This issue highlights the production of humanized skeletal muscle in human:pig chimaeras, skeletal muscle regeneration via the chemical induction and expansion of myogenic stem cells, the regeneration of infarcted mouse hearts via the direct reprogramming of mouse fibroblasts, the reprogramming of tumour cells into cancer stem cells on hydrogels, a protocol for the expansion of human limb-bud-like mesenchymal cells forming cartilaginous-like tissue, and various microphysiological systems for the identification of candidate antiviral therapeutics, for the modelling of fungal infection of the brain, for the evaluation of stem cell therapies for ischaemic stroke, and for the characterization of the differentiation of pluripotent stem cells into pancreatic duct-like organoids.

The cover illustrates a neurovascular-unit-on-a-chip with a functional blood–brain barrier for the recapitulation of the neurotropism of the most common pathogen causing fungal meningitis.

See Kim et al.

Sensing deep-tissue physiology via wearable ultrasonic phased arrays

This issue highlights diagnostic assays and diagnostic devices for the detection of nucleic acids in saliva or other biofluids or of cancer biomarkers in blood, and portable or wearable diagnostic devices designed for the detection or monitoring of a variety of physiological signals.

The cover illustrates a prototype ultrasonic phased array for the monitoring of blood flows in deep tissues.

See Wang et al.

Diagnosis of COVID-19 pneumonia from chest X-rays via deep learning

This issue highlights the development and application of machine-learning models for a wide range of biomedical and clinical problems, in particular the measurement of retinal-vessel calibre in retinal photographs, the diagnosis of COVID-19 pneumonia from chest X-rays, the prediction of breast cancer risk from ultrasound images, the detection of chronic kidney disease and type-2 diabetes from retinal images, the prediction of one-year all-cause mortality from echocardiography videos, the optimization of therapeutic antibodies, and the acceleration of antimicrobial discovery.

The cover illustrates an automated deep-learning pipeline for the identification and discrimination of viral, non-viral and COVID-19 pneumonia from chest X-rays.

See Wang et al.

Prolonged immune activation via polymer–STING condensates

This issue highlights an albumin–IL-4 fusion protein that ameliorates experimental autoimmune encephalomyelitis, the potency of CAR-T cells targeting a nucleophosmin neoepitope for treating acute myeloid leukaemia, vaccination against leukaemia via the sustained release of co-encapsulated anti-PD-1 and a leukaemia-associated antigen, the generation of hypoimmunogenic T cells from engineered allogeneic human induced pluripotent stem cells, erythrocyte-anchored chemokine-encapsulating nanoparticles for treating lung metastases, the durable activation of innate immune pathways by a polyvalent STING agonist, and the design of host defence peptides that specifically target Mycobacterium tuberculosis.

The cover illustrates that a polymeric STING agonist can prolong the activation of innate-immunity pathways via the formation of condensates.

See Li et al.

Modelling the multiregional dynamics of stimulated brain networks

This issue highlights a mathematical model for quantifying the sensitivity of patients with cancer to checkpoint inhibitors, the identification of subtypes of psychiatric disorders from functional-connectivity patterns in resting-state electroencephalography, the prediction of multiregional brain-network dynamics in response to direct electrical stimulation, computational modelling for the optimization of treatment schedules for glioblastoma, and the identification of converging genetic and epigenetic drivers of paediatric acute lymphoblastic leukaemia via an information-theory analysis of DNA methylation.

The cover illustrates the predicted dynamics of large-scale brain networks during direct electrical stimulation.

See Yang et al.

Ultrafast ultrasound microscopy of deep brain vessels

This issue highlights transcranial ultrafast ultrasound localization microscopy of brain vasculature, a portable magnetic resonance imaging (MRI) scanner for the head, a portable magnetic-resonance sensor for the grading of liver steatosis, iron-oxide-coated dextran nanoparticles for high-resolution MRI, contrast agents that use AND-gate logic to enhance fluorescence-guided imaging, a contrast agent for MRI that crosses the blood–brain barrier and that is sensitive to electric fields, and a Perspective on technology for 3D pathology.

The cover illustrates the imaging of vasculature deep in the human brain at microscopic resolution via ultrafast ultrasound localization microscopy of intravenously injected microbubbles.

See Demené et al.

‘Hit and run’ genome editing forestalls macular degeneration

This issue highlights germline genome engineering in pigs to inactivate endogenous retroviruses and to improve compatibility with the human immune system, the prevention of wet age-related macular degeneration in mice via ‘hit-and-run’ genome editing, the sustained reversion of myotonic dystrophy type I in mice via the CRISPR-mediated targeting of toxic RNA repeats, base editing for vision restoration in mice with an inherited retinal disease, undetectable off-target mutations in the RNA and DNA of base-edited hepatocytes in mouse with phenylketonuria, and a web tool for the rapid design of prime-editing guide RNAs.

The cover illustrates that lentiviruses co-packaging SpCas9 mRNA and an expression cassette encoding for a guide RNA can transiently disrupt targeted disease-modifying genes.

See Ling et al.

Mechanotransduced chiroptical differentiation of neural stem cells

This issue highlights microfluidic assays for the quantification of cell migration and proliferation to categorize patients with glioblastoma, for tracking the expression of therapeutic protein targets in circulating tumour cells from patients, and for the real-time measurement of glucose and insulin continuously in mice. It also highlights microneedles for the quantification of protein biomarkers in interstitial fluid, the classification of T-cell activation by measuring autofluorescence lifetimes, the mechanopharmacological conditioning of human stromal cells to enhance vascular regeneration, and epigenetic effects of extracellular-matrix stiffness in gastric tumours.

The cover illustrates the differentiation of neural stem cells into neurons via the transduction of chiral photons into force by DNA-bridged chiral assemblies of gold nanoparticles entangled with the neurons’ cytoskeletal fibres.

See Qu et al.