Nature Biomedical Engineering最新文献

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. In mice with orthotopic oral cancer, messenger RNA-based radioprotection of normal tissue preserved the efficacy of radiation therapy. The strategy may be broadly applicable to the protection of healthy tissue from DNA-damaging agents.

The efficacy of bacteriophages in treating bacterial infections largely depends on the phages’ vitality, which is impaired when they are naturally released from their hosts, as well as by culture media, manufacturing processes and other insults. Here, by wrapping phage-invaded bacteria individually with a polymeric nanoscale coating to preserve the microenvironment on phage-induced bacterial lysis, we show that, compared with naturally released phages, which have severely degraded proteins in their tail, the vitality of phages isolated from polymer-coated bacteria is maintained. Such latent phages could also be better amplified, and they more efficiently bound and lysed bacteria when clearing bacterial biofilms. In mice with bacterially induced enteritis and associated arthritis, latent phages released from orally administered bacteria coated with a polymer that dissolves at neutral pH had higher bioavailability and led to substantially better therapeutic outcomes than the administration of uncoated phages.

Advancing the understanding of the various roles and components of the immune system requires sophisticated methods and technology for the detection of immune cells in their natural states. Recent advancements in the development of molecular probes for optical imaging have paved the way for non-invasive visualization and real-time monitoring of immune responses and functions. Here we discuss recent progress in the development of molecular probes for the selective imaging of specific immune cells. We emphasize the design principles of the probes and their comparative performance when using various optical modalities across disease contexts. We highlight molecular probes for imaging tumour-infiltrating immune cells, and their applications in drug screening and in the prediction of therapeutic outcomes of cancer immunotherapies. We also discuss the use of these probes in visualizing immune cells in atherosclerosis, lung inflammation, allograft rejection and other immune-related conditions, and the translational opportunities and challenges of using optical molecular probes for further understanding of the immune system and disease diagnosis and prognosis.

High-dimensional multiplexed imaging can reveal the spatial organization of tumour tissues at the molecular level. However, owing to the scale and information complexity of the imaging data, it is challenging to discover and thoroughly characterize the heterogeneity of tumour microenvironments. Here we show that self-supervised representation learning on data from imaging mass cytometry can be leveraged to distinguish morphological differences in tumour microenvironments and to precisely characterize distinct microenvironment signatures. We used self-supervised masked image modelling to train a vision transformer that directly takes high-dimensional multiplexed mass-cytometry images. In contrast with traditional spatial analyses relying on cellular segmentation, the vision transformer is segmentation-free, uses pixel-level information, and retains information on the local morphology and biomarker distribution. By applying the vision transformer to a lung-tumour dataset, we identified and validated a monocytic signature that is associated with poor prognosis.

The development and wider adoption of adoptive cell therapies is constrained by complex and costly manufacturing processes and by inconsistent efficacy across patients. Here we discuss how microfluidic and other fluidic devices can be implemented at each stage of cell manufacturing for adoptive cell therapies, from the harvesting and isolation of the cells to their editing, culturing and functional selection. We suggest that precise and controllable microfluidic systems can streamline the development of these therapies by offering scalability in cell production, bolstering the efficacy and predictability of the therapies and improving their cost-effectiveness and accessibility for broader populations of patients with cancer.

Gene therapies and cell therapies require precise, reversible and patient-friendly control over the production of therapeutic proteins. Here we present a fully human nitric-oxide-responsive gene-regulation system for the on-demand and localized release of therapeutic proteins through clinically licensed nitroglycerin patches. Designed for simplicity and robust human compatibility, the system incorporates human mitochondrial aldehyde dehydrogenase for converting nitroglycerin into nitric oxide, which then activates soluble guanylate cyclase to produce cyclic guanosine monophosphate, followed by protein kinase G to amplify the signal and to trigger target gene expression. In a proof-of-concept study, human cells expressing the nitroglycerin-responsive system were encapsulated and implanted subcutaneously in obese mice with type 2 diabetes. Transdermal nitroglycerin patches applied over the implant enabled the controlled and reversible production of glucagon-like peptide-1 throughout the 35-day experimental period, effectively restoring blood glucose levels in these mice without affecting heart rate or blood pressure. The approach may facilitate the development of safe, convenient and responsive implantable devices for the sustained delivery of biopharmaceuticals for the management of chronic diseases.

In serology, each sample is typically tested individually, one antigen at a time. This is costly and time consuming. Serology techniques should ideally allow recurrent measurements in parallel in small sample volumes and be inexpensive and fast. Here we show that mass cytometry can be used to scale up multiplexed serology testing by leveraging polystyrene beads uniformly loaded with combinations of stable isotopes. We generated 18,480 unique isotopically barcoded beads to simultaneously detect, in a single tube with 924 serum samples, the levels of immunoglobulins G and M against 19 proteins from SARS-CoV-2 (a total of 36,960 tests in 400 nl of sample volume and 30 μl of reaction volume). As a rapid, high-throughput and cost-effective technique, serology by mass cytometry may contribute to the effective management of public health emergencies originating from infectious diseases.

Patient responses to immune checkpoint inhibitors can be influenced by the gastrointestinal microbiome. Mouse models can be used to study microbiome–host crosstalk, yet their utility is constrained by substantial anatomical, functional, immunological and microbial differences between mice and humans. Here we show that a gut-on-a-chip system mimicking the architecture and functionality of the human intestine by including faecal microbiome and peristaltic-like movements recapitulates microbiome–host interactions and predicts responses to immune checkpoint inhibitors in patients with melanoma. The system is composed of a vascular channel seeded with human microvascular endothelial cells and an intestinal channel with intestinal organoids derived from human induced pluripotent stem cells, with the two channels separated by a collagen matrix. By incorporating faecal samples from patients with melanoma into the intestinal channel and by performing multiomic analyses, we uncovered epithelium-specific biomarkers and microbial factors that correlate with clinical outcomes in patients with melanoma and that the microbiome of non-responders has a reduced ability to buffer cellular stress and self-renew. The gut-on-a-chip model may help identify prognostic biomarkers and therapeutic targets.