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Nanobiotechnology has the potential to enable smart plant sensors that communicate with and actuate electronic devices for improving plant productivity, optimize and automate water and agrochemical allocation, and enable high-throughput plant chemical phenotyping. Reducing crop loss due to environmental and pathogen-related stresses, improving resource use efficiency and selecting optimal plant traits are major challenges in plant agriculture industries worldwide. New technologies are required to accurately monitor, in real time and with high spatial and temporal resolution, plant physiological and developmental responses to their microenvironment. Nanomaterials are allowing the translation of plant chemical signals into digital information that can be monitored by standoff electronic devices. Herein, we discuss the design and interfacing of smart nanobiotechnology-based sensors that report plant signalling molecules associated with health status to agricultural and phenotyping devices via optical, wireless or electrical signals. We describe how nanomaterial-mediated delivery of genetically encoded sensors can act as tools for research and development of smart plant sensors. We assess performance parameters of smart nanobiotechnology-based sensors in plants (for example, resolution, sensitivity, accuracy and durability) including in vivo optical nanosensors and wearable nanoelectronic sensors. To conclude, we present an integrated and prospective vision on how nanotechnology could enable smart plant sensors that communicate with and actuate electronic devices for monitoring and optimizing individual plant productivity and resource use.Nanotechnology can be used to create smart plant sensors that could eventually improve agricultural productivity.

Pre-eclampsia is a placental disorder that affects 3–5% of all pregnancies and is a leading cause of maternal and fetal morbidity worldwide 1 , 2 . With no drug available to slow disease progression, engineering ionizable lipid nanoparticles (LNPs) for extrahepatic messenger RNA (mRNA) delivery to the placenta is an attractive therapeutic option for pre-eclampsia. Here we use high-throughput screening to evaluate a library of 98 LNP formulations in vivo and identify a placenta-tropic LNP (LNP 55) that mediates more than 100-fold greater mRNA delivery to the placenta in pregnant mice than a formulation based on the Food and Drug Administration-approved Onpattro LNP (DLin-MC3-DMA) 3 . We propose an endogenous targeting mechanism based on β 2 -glycoprotein I adsorption that enables LNP delivery to the placenta. In both inflammation- and hypoxia-induced models of pre-eclampsia, a single administration of LNP 55 encapsulating vascular endothelial growth factor (VEGF) mRNA resolves maternal hypertension until the end of gestation. In addition, with our VEGF mRNA LNP 55 therapeutic, we demonstrate improvements in fetal health and partially restore placental vasculature, the local and systemic immune landscape and serum levels of soluble Fms-like tyrosine kinase-1, a clinical biomarker of pre-eclampsia 1 . Together, these results demonstrate the potential of this mRNA LNP platform for treating placental disorders such as pre-eclampsia. A platform for mRNA lipid nanoparticle delivery to the placenta to treat pre-eclampsia is shown to improve fetal and maternal health in mice and has potential clinical applications in obstetric disorders and women’s health.

Cancer recurrence after surgical resection remains a significant cause of treatment failure. Here, we have developed an in situ formed immunotherapeutic bioresponsive gel that controls both local tumour recurrence after surgery and development of distant tumours. Briefly, calcium carbonate nanoparticles pre-loaded with the anti-CD47 antibody are encapsulated in the fibrin gel and scavenge H+ in the surgical wound, allowing polarization of tumour-associated macrophages to the M1-like phenotype. The released anti-CD47 antibody blocks the ‘don’t eat me’ signal in cancer cells, thereby increasing phagocytosis of cancer cells by macrophages. Macrophages can promote effective antigen presentation and initiate T cell mediated immune responses that control tumour growth. Our findings indicate that the immunotherapeutic fibrin gel ‘awakens’ the host innate and adaptive immune systems to inhibit both local tumour recurrence post surgery and potential metastatic spread.

Cell-imprinted polydimethylsiloxane substrates, in terms of their ability to mimic the physiological niche, low microfabrication cost, and excellent biocompatibility were widely used in tissue engineering. Cells inside the mature cells' cell-imprinted PDMS pattern have been shown in previous research to be capable of being differentiated into a specific mature cell line. On the other hand, the hydrophobicity of PDMS substrate leads to weak cell adhesion. Moreover, there was no guarantee that the cells would be exactly located in the cavities of the cells' pattern. In many studies, PDMS surface was modified by plasma treatment, chemical modification, and ECM coating. Hence, to increase the efficiency of cell-imprinting method, the concavity region created by the cell-imprinted pattern is conjugated with collagen. A simple and economical method of epoxy silane resin was applied for the selective protein immobilization on the desired regions of the PDMS substrate. This method could be paved to enhance the cell trapping into the cell-imprinted pattern, and it could be helpful for stem cell differentiation studies. The applied method for selective protein attachment, and as a consequence, selective cell integration was assessed on the aligned cell-imprinted PDMS. A microfluidic chip created the aligned cell pattern. After Ar + plasma and APTES treatment of the PDMS substrate, collagen immobilization was performed. The immobilized collagen was removed by epoxy silane resin stamp from the ridge area where the substrate lacked cell pattern and leaving the collagen only within the patterned areas. Coomassie brilliant blue staining was evaluated for selective collagen immobilization, and the collagen-binding stability was assessed by BCA analysis. MTT assay for the evaluation of cell viability on the modified surface was further analyzed. Subsequently, the crystal violet staining has confirmed the selective cell integration to the collagen-immobilized site on the PDMS substrate. The results proved the successfully selective collagen immobilization on the cell-imprinted PDMS and showed that this method increased the affinity of cells to attach inside the cell pattern cavity.

RNA interference (RNAi) is an ancient biological mechanism used to defend against external invasion. It theoretically can silence any disease-related genes in a sequence-specific manner, making small interfering RNA (siRNA) a promising therapeutic modality. After a two-decade journey from its discovery, two approvals of siRNA therapeutics, ONPATTRO® (patisiran) and GIVLAARI™ (givosiran), have been achieved by Alnylam Pharmaceuticals. Reviewing the long-term pharmaceutical history of human beings, siRNA therapy currently has set up an extraordinary milestone, as it has already changed and will continue to change the treatment and management of human diseases. It can be administered quarterly, even twice-yearly, to achieve therapeutic effects, which is not the case for small molecules and antibodies. The drug development process was extremely hard, aiming to surmount complex obstacles, such as how to efficiently and safely deliver siRNAs to desired tissues and cells and how to enhance the performance of siRNAs with respect to their activity, stability, specificity and potential off-target effects. In this review, the evolution of siRNA chemical modifications and their biomedical performance are comprehensively reviewed. All clinically explored and commercialized siRNA delivery platforms, including the GalNAc (N-acetylgalactosamine)–siRNA conjugate, and their fundamental design principles are thoroughly discussed. The latest progress in siRNA therapeutic development is also summarized. This review provides a comprehensive view and roadmap for general readers working in the field.

Chimeric antigen receptor (CAR)-T-cell therapy for solid tumors is limited due to heterogeneous target antigen expression and outgrowth of tumors lacking the antigen targeted by CAR-T cells directed against single antigens. Here, we developed a bicistronic construct to drive expression of a CAR specific for EGFRvIII, a glioblastoma-specific tumor antigen, and a bispecific T-cell engager (BiTE) against EGFR, an antigen frequently overexpressed in glioblastoma but also expressed in normal tissues. CART.BiTE cells secreted EGFR-specific BiTEs that redirect CAR-T cells and recruit untransduced bystander T cells against wild-type EGFR. EGFRvIII-specific CAR-T cells were unable to completely treat tumors with heterogenous EGFRvIII expression, leading to outgrowth of EGFRvIII-negative, EGFR-positive glioblastoma. However, CART.BiTE cells eliminated heterogenous tumors in mouse models of glioblastoma. BiTE-EGFR was locally effective but was not detected systemically after intracranial delivery of CART.BiTE cells. Unlike EGFR-specific CAR-T cells, CART.BiTE cells did not result in toxicity against human skin grafts in vivo. BiTE-secreting CAR-T cells overcome antigen escape from EGFRvIII-targeted therapy for glioblastoma.

Oral administration provides a simple and non-invasive approach for drug delivery. However, due to poor absorption and swift enzymatic degradation in the gastrointestinal tract, a wide range of molecules must be parenterally injected to attain required doses and pharmacokinetics. Here we present an orally dosed liquid auto-injector capable of delivering up to 4-mg doses of a bioavailable drug with the rapid pharmacokinetics of an injection, reaching an absolute bioavailability of up to 80% and a maximum plasma drug concentration within 30 min after dosing. This approach improves dosing efficiencies and pharmacokinetics an order of magnitude over our previously designed injector capsules and up to two orders of magnitude over clinically available and preclinical chemical permeation enhancement technologies. We administered the capsules to swine for delivery of clinically relevant doses of four commonly injected medications, including adalimumab, a GLP-1 analog, recombinant human insulin and epinephrine. These multi-day dosing experiments and oral administration in awake animal models support the translational potential of the system. Biologics are delivered by a pill that pricks the stomach wall.

Despite recent improvements in sequencing methods, there remains a need for assays that provide high sequencing depth and comprehensive variant detection. Current methods 1 – 4 are limited by the loss of native modifications, short read length, high input requirements, low yield or long protocols. In the present study, we describe nanopore Cas9-targeted sequencing (nCATS), an enrichment strategy that uses targeted cleavage of chromosomal DNA with Cas9 to ligate adapters for nanopore sequencing. We show that nCATS can simultaneously assess haplotype-resolved single-nucleotide variants, structural variations and CpG methylation. We apply nCATS to four cell lines, to a cell-line-derived xenograft, and to normal and paired tumor/normal primary human breast tissue. Median sequencing coverage was 675× using a MinION flow cell and 34× using the smaller Flongle flow cell. The nCATS sequencing requires only ~3 μg of genomic DNA and can target a large number of loci in a single reaction. The method will facilitate the use of long-read sequencing in research and in the clinic. Point mutations, structural variants and DNA methylation at target loci are assessed by nanopore sequencing.

High-throughput quantification of protein and gene expression in single cells is achieved using DNA-barcoded antibodies. We present a tool to measure gene and protein expression levels in single cells with DNA-labeled antibodies and droplet microfluidics. Using the RNA expression and protein sequencing assay (REAP-seq), we quantified proteins with 82 barcoded antibodies and >20,000 genes in a single workflow. We used REAP-seq to assess the costimulatory effects of a CD27 agonist on human CD8 + lymphocytes and to identify and characterize an unknown cell type.

A limitation of spatial transcriptomics technologies is that individual measurements may contain contributions from multiple cells, hindering the discovery of cell-type-specific spatial patterns of localization and expression. Here, we develop robust cell type decomposition (RCTD), a computational method that leverages cell type profiles learned from single-cell RNA-seq to decompose cell type mixtures while correcting for differences across sequencing technologies. We demonstrate the ability of RCTD to detect mixtures and identify cell types on simulated datasets. Furthermore, RCTD accurately reproduces known cell type and subtype localization patterns in Slide-seq and Visium datasets of the mouse brain. Finally, we show how RCTD’s recovery of cell type localization enables the discovery of genes within a cell type whose expression depends on spatial environment. Spatial mapping of cell types with RCTD enables the spatial components of cellular identity to be defined, uncovering new principles of cellular organization in biological tissue. RCTD is publicly available as an open-source R package at https://github.com/dmcable/RCTD . Cell type mapping in spatial transcriptomics is enabled by accounting for compositional mixtures and differences in sequencing technologies.