Nature Biomedical Engineering最新文献

Optimization of oncolytic viruses for therapeutic applications requires the strategic removal or mutagenesis of virulence genes alongside the insertion of transgenes that enhance viral replication, spread and immunogenicity. However, the complexity of many viral genomes and the labour-intensive nature of methods for the generation and isolation of recombinant viruses have hindered the development of therapeutic oncolytic viruses. Here we report an iterative strategy that exploits the preferential susceptibility of viruses to certain antibiotics to accelerate the engineering of the genomes of oncolytic viruses for the insertion of immunomodulatory cytokine transgenes, and the identification of dispensable genes with regard to replication of the recombinant oncolytic viruses in tumour cells. We applied the strategy by leveraging insertional mutagenesis via the Sleeping Beauty transposon system, combined with long-read nanopore sequencing, to generate libraries of herpes simplex virus type 1 and vaccinia virus, identifying stable transgene insertion sites and gene deletions that enhance the safety and efficacy of the viruses.

The activation of cytotoxic T cells against tumour cells typically requires the cross-presentation, by antigen-presenting cells (and via major histocompatibility complex class I molecules), of an epitope derived from a tumour antigen. A critical step in antigen processing is the proteolysis of tumour antigens mediated by the ubiquitin–proteasome pathway. Here we describe a tumour vaccine leveraging targeted antigen degradation to augment antigen processing and cross-presentation. Analogous to proteolysis-targeting chimaeras, the vaccine consists of lymph-node-targeting lipid nanoparticles encapsulated with tumour antigens pre-conjugated with ligands that can bind to E3 ubiquitin ligases. In mice with subcutaneous human melanoma or triple-negative breast cancer, or with orthotopic mouse Lewis lung carcinoma or clinically inoperable mouse ovarian cancer, subcutaneously delivered vaccines prepared using tumour lysate proteins elicited antigen-specific adaptive immunity and immunological memory, and inhibited tumour growth, metastasis and recurrence, particularly when combined with immune checkpoint inhibition.

Diagnostic kits for the optical detection of bladder cancer in urine can facilitate effective screening and surveillance. However, the heterogeneity of urine samples, owing to patients with bladder cancer often presenting with haematuria, interfere with the transduction of the optical signal. Here we describe the development and point-of-care performance of a device for the detection of bladder cancer that obviates the need for sample processing. The device leverages the enzymatic release of organogel particles carrying solvatochromic fluorophores in the presence of urinary hyaluronidases—a bladder cancer biomarker. Owing to buoyancy, the particles transfer from the urine sample into the organic phase, where the change in fluorescence can be measured via a smartphone without interference from blood proteins. In a double-blind study with 80 unprocessed urine samples from patients with bladder cancer (including samples with haematuria) or other genitourinary diseases and with 25 samples from healthy participants, our system distinguished the cancerous samples, including those with early-stage bladder cancer, with accuracies of about 90%. Obviating the need for sample pretreatment may facilitate the at-home detection of bladder cancer.

Activation of the ion channel transient receptor potential vanilloid 1 (TRPV1), which is integral to pain perception, leads to an expansion of channel width, facilitating the passage of cations and large organic molecules. However, the permeability of TRPV1 channels to water remains uncertain, owing to a lack of suitable tools to study water dynamics. Here, using upconversion nanophosphors to discriminate between H₂O and D₂O, by monitoring water permeability across activated TRPV1 at the single-cell and single-molecule levels, and by combining single-channel current measurements with molecular dynamics simulations, we show that water molecules flow through TRPV1 and reveal a direct connection between water migration, cation flow and TRPV1 functionality. We also show in mouse models of acute or chronic inflammatory pain that the administration of deuterated water suppresses TRPV1 activity, interrupts the transmission of pain signals and mitigates pain without impacting other neurological responses. Solvent-mediated analgesia may inspire alternative options for pain management.

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. Wearable ultrasound for the continuous and non-invasive monitoring of blood pressure promises to elevate the quality of patient care, yet the isolated sonographic windows in the most advanced prototypes can lead to inaccurate or error-prone measurements, and the safety and performance of these devices have not been thoroughly evaluated. Here we describe validation studies, conducted during daily activities at home, in the outpatient clinic, in the cardiac catheterization laboratory and in the intensive care unit, of the safety and performance of a wearable ultrasound sensor for blood pressure monitoring. The sensor has closely connected sonographic windows and a backing layer that improves the sensor’s accuracy and reliability to meet the highest requirements of clinical standards. The validation results support the clinical use of the sensor.