Engineered bacteria launch and control an oncolytic virus.

The ability of bacteria and viruses to selectively replicate in tumours has led to synthetic engineering of new microbial therapies. Here we design a cooperative strategy whereby Salmonella typhimurium bacteria transcribe and deliver the Senecavirus A RNA genome inside host cells, launching a potent oncolytic viral infection. 'Encapsidated' by bacteria, the viral genome can further bypass circulating antiviral antibodies to reach the tumour and initiate replication and spread within immune mice.

Mechanical regulation of extracellular vesicle activity during tumour progression.

Extracellular vesicles (EVs) are naturally occurring membrane-bound vesicles secreted by cells. Functionalized with surface-targeting molecules and carrying signalling proteins and nucleic acids as cargo, EVs can rewire pathways and alter biological processes in recipient cells. Tumour-derived EVs have key roles in cancer progression, particularly in metastasis, by promoting tumour cell invasion and the establishment of pre-metastatic niches.

Tumour-resident oncolytic bacteria trigger potent anticancer effects through selective intratumoural thrombosis and necrosis.

Intratumoural bacteria represent a promising drug-free strategy in cancer therapy. Here we demonstrate that a tumour-resident bacterial consortium-Proteus mirabilis (A-gyo) and Rhodopseudomonas palustris (UN-gyo)-in a precise 3:97 ratio (A-gyo:UN-gyo), exhibits potent antitumour efficacy independent of immune cell infiltration. In both immunocompetent and immunocompromised mouse models, including human tumour xenografts, intravenous administration of the bacterial consortium led to complete tumour remission, prolonged survival, and no observable systemic toxicity or cytokine release syndrome.

Vaccination with an mRNA-encoded membrane-bound HIV envelope trimer induces neutralizing antibodies in animal models.

A protective vaccine against human immunodeficiency virus (HIV) will likely need to induce broadly neutralizing antibodies (bnAbs) that engage relatively conserved epitopes on the HIV envelope glycoprotein (Env) trimer. Nearly all vaccine strategies to induce bnAbs require the use of complex immunization regimens involving a series of different immunogens, most of which are Env trimers. Producing protein-based clinical material to evaluate such relatively complex regimens in humans presents major challenges in cost and time.

Global Estimates of Lives and Life-Years Saved by COVID-19 Vaccination During 2020-2024.

Importance: Estimating global lives and life-years saved is important to put into perspective the benefits of COVID-19 vaccination. Prior studies have focused mainly on the pre-Omicron period or only on specific regions, and lack crucial life-year calculations and often depend on strong modeling assumptions with unaccounted uncertainty.

Objective: To calculate the lives and life-years saved by COVID-19 vaccination worldwide from the onset of the vaccination campaigns and until October 1, 2024.

Floss-based vaccination targets the gingival sulcus for mucosal and systemic immunization.

The oral cavity is an accessible site for vaccination, but its sublingual and buccal sites have limited vaccine uptake. Here we show that flat tape dental floss can deliver vaccines through the junctional epithelium of the gingival sulcus, exploiting its naturally leaky properties. Floss-based vaccination delivered protein, inactivated virus, peptide-presenting immunogenic nanoparticles and messenger RNA.

Sensitization of tumours to immunotherapy by boosting early type-I interferon responses enables epitope spreading.

The success of cancer immunotherapies is predicated on the targeting of highly expressed neoepitopes, which preferentially favours malignancies with high mutational burden. Here we show that early responses by type-I interferons mediate the success of immune checkpoint inhibitors as well as epitope spreading in poorly immunogenic tumours and that these interferon responses can be enhanced via systemic administration of lipid particles loaded with RNA coding for tumour-unspecific antigens. In mice, the immune responses of tumours sensitive to checkpoint inhibitors were transferable to resistant tumours and resulted in heightened immunity with antigenic spreading that protected the animals from tumour rechallenge.

Picoeukaryote-based biohybrid microrobots for active delivery in the kidney.

Confined spaces in the human body pose substantial challenges for biomedical procedures. Navigating these ultrasmall environments is essential for precise drug delivery, improving treatment outcomes and reducing adverse effects. Microrobots offer a promising approach to accessing these complex microenvironments.

PET-based tracking of CAR T cells and viral gene transfer using a cell surface reporter that binds to lanthanide complexes.

The clinical translation of cell- and gene-based therapies is limited by the lack of non-invasive, quantitative and specific whole-body imaging tools. Here we present a positron emission tomography reporter system based on a membrane-anchored anticalin protein that binds a fluorine-18-labelled lanthanide complex with picomolar affinity via a bio-orthogonal interaction. The reporter was introduced into therapeutic cells, including CAR T cells and adeno-associated virus-transduced cells.

A live bacteria enzyme assay for identification of human disease mutations and drug screening.

Advances in high-throughput sequencing have enabled the identification of genetic variations associated with human disease. However, deciphering the functional significance of these variations remains challenging. Here we propose an alternative approach that uses humanized Escherichia coli to study human genetic enzymopathies and to screen candidate drug effects on metabolic targets.

3D-printed perfused models of the penis for the study of penile physiology and for restoring erectile function in rabbits and pigs.

The intricate topology of vascular networks and the complex functions of vessel-rich tissues are challenging to reconstruct in vitro. Here we report the development of: in vitro pathological models of erectile dysfunction and Peyronie's disease; a model of the penis that includes the glans and the corpus spongiosum with urethral structures; and an implantable model of the corpus cavernosum, whose complex vascular network is critical for erectile function, via the vein-occlusion effect. Specifically, we 3D printed a hydrogel-based corpus cavernosum incorporating a strain-limiting tunica albuginea that can be engorged with blood through vein occlusion.

Radioprotection of healthy tissue via nanoparticle-delivered mRNA encoding for a damage-suppressor protein found in tardigrades.

Patients undergoing radiation therapy experience debilitating side effects because of toxicity arising from radiation-induced DNA strand breaks in normal peritumoural cells. Here, inspired by the ability of tardigrades to resist extreme radiation through the expression of a damage-suppressor protein that binds to DNA and reduces strand breaks, we show that the local and transient expression of the protein can reduce radiation-induced DNA damage in oral and rectal epithelial tissues (which are commonly affected during radiotherapy for head-and-neck and prostate cancers, respectively). We used ionizable lipid nanoparticles supplemented with biodegradable cationic polymers to enhance the transfection efficiency and delivery of messenger RNA encoding the damage-suppressor protein into buccal and rectal tissues.

Synaptic connectivity mapping among thousands of neurons via parallelized intracellular recording with a microhole electrode array.

The massive parallelization of neuronal intracellular recording, which enables the measurement of synaptic signals across a neuronal network, and thus the mapping and characterization of synaptic connections, is an open challenge, with the state of the art being limited to the mapping of about 300 synaptic connections. Here we report a 4,096 platinum/platinum-black microhole electrode array fabricated on a complementary metal-oxide semiconductor chip for parallel intracellular recording and thus for synaptic-connectivity mapping. The microhole-neuron interface, together with current-clamp electronics in the underlying semiconductor chip, allowed a 90% average intracellular coupling rate in rat neuronal cultures, generating network-wide intracellular-recording data with abundant synaptic signals.

Leucine zipper-based immunomagnetic purification of CAR T cells displaying multiple receptors.

Resistance to chimaeric antigen receptor (CAR) T cell therapy develops through multiple mechanisms, most notably antigen loss and tumour-induced immune suppression. It has been suggested that T cells expressing multiple CARs may overcome the resistance of tumours and that T cells expressing receptors that switch inhibitory immune-checkpoint signals into costimulatory signals may enhance the activity of the T cells in the tumour microenvironment. However, engineering multiple features into a single T cell product is difficult because of the transgene-packaging constraints of current gene-delivery vectors.

Clinical validation of a wearable ultrasound sensor of blood pressure.

Options for the continuous and non-invasive monitoring of blood pressure are limited. Cuff-based sphygmomanometers are widely available, yet provide only discrete measurements. The clinical gold-standard approach for the continuous monitoring of blood pressure requires an arterial line, which is too invasive for routine use.

Systemically injected oxygen within rapidly dissolving microbubbles improves the outcomes of severe hypoxaemia in swine.

Acute respiratory failure can cause profound hypoxaemia that leads to organ injury or death within minutes. When conventional interventions are ineffective, the intravenous administration of oxygen can rescue patients from severe hypoxaemia, but at the risk of microvascular obstruction and of toxicity of the carrier material. Here we describe polymeric microbubbles as carriers of high volumes of oxygen (350-500 ml of oxygen per litre of foam) that are stable in storage yet quickly dissolve following intravenous injection, reverting to their soluble and excretable molecular constituents.

Low-cost and scalable projected light-sheet microscopy for the high-resolution imaging of cleared tissue and living samples.

Light-sheet fluorescence microscopy (LSFM) is a widely used technique for imaging cleared tissue and living samples. However, high-performance LSFM systems are typically expensive and not easily scalable. Here we introduce a low-cost, scalable and versatile LSFM framework, which we named 'projected light-sheet microscopy' (pLSM), with high imaging performance and small device and computational footprints.

A bilingual speech neuroprosthesis driven by cortical articulatory representations shared between languages.

Advancements in decoding speech from brain activity have focused on decoding a single language. Hence, the extent to which bilingual speech production relies on unique or shared cortical activity across languages has remained unclear. Here, we leveraged electrocorticography, along with deep-learning and statistical natural-language models of English and Spanish, to record and decode activity from speech-motor cortex of a Spanish-English bilingual with vocal-tract and limb paralysis into sentences in either language.

Week-long normoglycaemia in diabetic mice and minipigs via a subcutaneous dose of a glucose-responsive insulin complex.

Glucose-responsive formulations of insulin can increase its therapeutic index and reduce the burden of its administration. However, it has been difficult to develop single-dosage formulations that can release insulin in both a sustained and glucose-responsive manner. Here we report the development of a subcutaneously injected glucose-responsive formulation that nearly does not trigger the formation of a fibrous capsule and that leads to week-long normoglycaemia and negligible hypoglycaemia in mice and minipigs with type 1 diabetes.

In-ear integrated sensor array for the continuous monitoring of brain activity and of lactate in sweat.

Owing to the proximity of the ear canal to the central nervous system, in-ear electrophysiological systems can be used to unobtrusively monitor brain states. Here, by taking advantage of the ear's exocrine sweat glands, we describe an in-ear integrated array of electrochemical and electrophysiological sensors placed on a flexible substrate surrounding a user-generic earphone for the simultaneous monitoring of lactate concentration and brain states via electroencephalography, electrooculography and electrodermal activity. In volunteers performing an acute bout of exercise, the device detected elevated lactate levels in sweat concurrently with the modulation of brain activity across all electroencephalography frequency bands.

Synthetically glycosylated antigens for the antigen-specific suppression of established immune responses.

Inducing antigen-specific tolerance during an established immune response typically requires non-specific immunosuppressive signalling molecules. Hence, standard treatments for autoimmunity trigger global immunosuppression. Here we show that established antigen-specific responses in effector T cells and memory T cells can be suppressed by a polymer glycosylated with N-acetylgalactosamine (pGal) and conjugated to the antigen via a self-immolative linker that allows for the dissociation of the antigen on endocytosis and its presentation in the immunoregulatory environment.

Computational optimization of antibody humanness and stability by systematic energy-based ranking.

Conventional methods for humanizing animal-derived antibodies involve grafting their complementarity-determining regions onto homologous human framework regions. However, this process can substantially lower antibody stability and antigen-binding affinity, and requires iterative mutational fine-tuning to recover the original antibody properties. Here we report a computational method for the systematic grafting of animal complementarity-determining regions onto thousands of human frameworks.

A swallowable X-ray dosimeter for the real-time monitoring of radiotherapy.

Monitoring X-ray radiation in the gastrointestinal tract can enhance the precision of radiotherapy in patients with gastrointestinal cancer. Here we report the design and performance, in the gastrointestinal tract of rabbits, of a swallowable X-ray dosimeter for the simultaneous real-time monitoring of absolute absorbed radiation dose and of changes in pH and temperature. The dosimeter consists of a biocompatible optoelectronic capsule containing an optical fibre, lanthanide-doped persistent nanoscintillators, a pH-sensitive polyaniline film and a miniaturized system for the wireless readout of luminescence.

Immunization against Zika by entrapping live virus in a subcutaneous self-adjuvanting hydrogel.

The threat of new viral outbreaks has heightened the need for ready-to-use vaccines that are safe and effective. Here we show that a subcutaneous vaccine consisting of live Zika virus electrostatically entrapped in a self-adjuvanting hydrogel recruited immune cells at the injection site and provided mice with effective protection against a lethal viral challenge. The hydrogel prevented the escape of the viral particles and upregulated pattern recognition receptors that activated innate antiviral immunity.

Multi-antigen spherical nucleic acid cancer vaccines.

Cancer vaccines must activate multiple immune cell types to be effective against aggressive tumours. Here we report the impact of the structural presentation of two antigenic peptides on immune responses at the transcriptomic, cellular and organismal levels. We used spherical nucleic acid (SNA) nanoparticles to investigate how the spatial distribution and placement of two antigen classes affect antigen processing, cytokine production and the induction of memory.