Although immunotherapy has benefited a subset of persons with cancer, its broader efficacy remains limited, primarily because of an immunosuppressive tumor microenvironment characterized by insufficient numbers of functional tumor-specific T cells, antigen-presenting cells (APCs) and tumor-infiltrating lymphocytes. Here we engineer immune cells in the tumor microenvironment using lipid nanoparticles (LNPs) to deliver immune-remodeling mRNAs (IR-mRNAs) encoding NF-κB-inducing kinase or interferon regulatory factor 8. These IR-mRNAs activate APCs in tumors, significantly increasing activated type 1 conventional dendritic cells, immunostimulatory cytokines and priming antitumor CD8+ T cells. IR-mRNAs encapsulated in LNPs elicited durable antitumor responses in multiple syngeneic mouse tumor models through both intratumoral and intravenous delivery. Coadministration of IR-mRNA and ovalbumin mRNA elicited a ~10-fold increase in antigen-specific CD8+ T cell responses, sustained long-term memory and effectively prevented tumor growth in vaccinated mice. Additionally, coadministration of IR-mRNA and hemagglutinin mRNA enhanced the humoral response ~5-fold and the cellular response ~15-fold, underscoring their potential as adjuvants for boosting adaptive immunity.

The blood-brain barrier (BBB) restricts the systemic delivery of messenger RNAs (mRNAs) into diseased neurons. Although leucocyte-derived extracellular vesicles (EVs) can cross the BBB at inflammatory sites, it is difficult to efficiently load long mRNAs into the EVs and to enhance their neuronal uptake. Here we show that the packaging of mRNA into leucocyte-derived EVs and the endocytosis of the EVs by neurons can be enhanced by engineering leucocytes to produce EVs that incorporate retrovirus-like mRNA-packaging capsids. We transfected immortalized and primary bone-marrow-derived leucocytes with DNA or RNA encoding the capsid-forming activity-regulated cytoskeleton-associated (Arc) protein as well as capsid-stabilizing Arc 5'-untranslated-region RNA elements. These engineered EVs inherit endothelial adhesion molecules from donor leukocytes, recruit endogenous enveloping proteins to their surface, cross the BBB, and enter the neurons in neuro-inflammatory sites. Produced from self-derived donor leukocytes, the EVs are immunologically inert, and enhanced the neuronal uptake of the packaged mRNA in a mouse model of low-grade chronic neuro-inflammation.

Medical interventions often require timed series of doses, thus necessitating accurate medical record-keeping. In many global settings, these records are unreliable or unavailable at the point of care, leading to less effective treatments or disease prevention. Here we present an invisible-to-the-naked-eye on-patient medical record-keeping technology that accurately stores medical information in the patient skin as part of microneedles that are used for intradermal therapeutics. We optimize the microneedle design for both a reliable delivery of messenger RNA (mRNA) therapeutics and the near-infrared fluorescent microparticles that encode the on-patient medical record-keeping. Deep learning-based image processing enables encoding and decoding of the information with excellent temporal and spatial robustness. Long-term studies in a swine model demonstrate the safety, efficacy and reliability of this approach for the co-delivery of on-patient medical record-keeping and the mRNA vaccine encoding severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This technology could help healthcare workers make informed decisions in circumstances where reliable record-keeping is unavailable, thus contributing to global healthcare equity.

The authors wish to add the following sentence into the ‘Competing interests’ section of this Article: “P.W.K. has investment interest in Context Therapeutics LLC, DRGT, Placon, Seer Biosciences and Tarveda Therapeutics, is a company board member for Context Therapeutics LLC, is a consultant and scientific advisory board member for BIND Biosciences, Inc., BN Immunotherapeutics, DRGT, GE Healthcare, Janssen, Metamark, New England Research Institutes, Inc., OncoCellMDX, Progenity, Sanofi, Seer Biosciences, Tarveda Therapeutics and Thermo Fisher, and serves on data safety monitoring boards for Genentech/Roche and Merck.” This has now been included.

The targeted delivery of immunotherapies to tumours using tumour-responsive nanomaterials is a promising area of cancer research with the potential to address the limitations of systemic administration such as on-target off-tumour toxicities and a lack of activity owing to the immunosuppressive tumour microenvironment (TME). Attempts to address these challenges include the design and functionalization of nanomaterials capable of releasing their cargoes in response to specific TME characteristics, thus facilitating the targeted delivery of immune-checkpoint inhibitors, cytokines, mRNAs, vaccines and, potentially, chimaeric antigen receptors as well as of agents that modulate the extracellular matrix and induce immunogenic cell death. In this Review, we describe these various research efforts in the context of the dynamic properties of the TME, such as pH, reductive conditions, reactive oxygen species, hypoxia, specific enzymes, high levels of ATP and locoregional aspects, which can be leveraged to enhance the specificity and efficacy of nanomaterial-based immunotherapies. Highlighting preclinical successes and ongoing clinical trials, we evaluate the current landscape and potential of these innovative approaches. We also consider future research directions as well as the most important barriers to successful clinical translation, emphasizing the transformative potential of tumour-responsive nanomaterials in overcoming the barriers that limit the activity of traditional immunotherapies, thus improving patient outcomes. Immunotherapies, predominantly immune-checkpoint inhibitors and chimaeric antigen receptor T cells, have transformed oncology. Nonetheless, these systemically administered agents have several limitations, including the risk of off-target toxicities and a lack of activity owing to an inability to overcome an immunosuppressive tumour microenvironment (TME). In this Review, the authors describe the potential to overcome these challenges using functionalized nanomaterials that are designed to release a wide range of immunotherapeutic cargoes in response to specific TME characteristics, including hypoxia, differences in pH, the presence of specific enzymes, reactive oxygen species and/or high levels of extracellular ATP.

Patient-specific, human-based cellular models integrating a biomimetic blood-brain barrier (BBB), immune, and myelinated neuron components are critically needed to enable accelerated, translationally relevant discovery of neurological disease mechanisms and interventions. By engineering a novel brain-mimicking 3D hydrogel and co-culturing all six major brain cell types derived from patient iPSCs, we have constructed, characterized, and utilized a multicellular integrated brain (miBrain) immuno-glial-neurovascular model with in vivo- like hallmarks inclusive of neuronal activity, functional connectivity, barrier function, myelin-producing oligodendrocyte engagement with neurons, multicellular interactions, and transcriptomic profiles. We implemented the model to study Alzheimer's Disease pathologies associated with APOE4 genetic risk. APOE4 miBrains differentially exhibit amyloid aggregation, tau phosphorylation, and astrocytic GFAP. Unlike the co-emergent fate specification of glia and neurons in organoids, miBrains integrate independently differentiated cell types, a feature we harnessed to identify that APOE4 in astrocytes promotes neuronal tau pathogenesis and dysregulation through crosstalk with microglia.

Endovascular embolization is a minimally-invasive technique whereby blood vessels supplying pathological structures are selectively occluded with various embolic agents. In many scenarios, it is desirable for the embolic to distally penetrate to the level of the microvasculature, which maximizes devascularization. Existing agents exhibit inconsistent distal penetration and have other limitations including tendency for proximal reflux, patient pain during infusion, lack of fluoroscopic radiopacity, potential for catheter adhesion, susceptibility to recanalization, and other usability challenges. NeoCast is an in situ curing, solvent-free, non-adhesive biomaterial composed of polydimethylsiloxane, bismuth trioxide, and fumed silica that possesses shear-responsive properties enabling manual injectability through commercially-available microcatheters with large and small diameter lumens. Here, embolization performance with and without flow arrest, in both arterial and venous preclinical anatomies is reported. NeoCast reproducibly achieves a rate of distal penetration with microvascular occlusion that is superior to existing agents, exhibits excellent fluoroscopic visibility, and provides durable occlusion. There is mild inflammation when NeoCast is infused into blood vessels and absence of neurotoxicity when implanted directly into brain tissue. The engineered NeoCast material is poised to become a next-generation, liquid embolic agent for applications in which distal microvascular occlusion is desired.

Nanoparticles formulated with certain cationic lipids or polymers have been shown to facilitate RNA delivery to the endothelium. Here, we show that these nanoparticles become coated with coagulating proteins and induce coagulation for RNA delivery in vivo, without leading to histological evidence of clot formation. We further show that nanoparticles previously reported to transfect the liver can be redirected to other organs by preincubating them with procoagulant proteins. Our data demonstrate that activation of the coagulation cascade mediates endothelial RNA delivery and indicate that nanoparticles can be targeted to the endothelium of various organs by integrating procoagulant components in their formulation.

We report plasmonic gold nanoshells and nanorods coated with reduced graphene oxide that produce an enhanced photothermal effect when stimulated by near-infrared (NIR) light. Electrostatic interactions between nanosized graphene oxide and gold nanoparticles followed by in situ chemical reduction generated reduced graphene oxide-coated nanoparticles; the coating was demonstrated using Raman and HR-TEM. Reduced graphene oxide-coated gold nanoparticles showed enhanced photothermal effect compared to noncoated or nonreduced graphene oxide-coated gold nanoparticles. Reduced graphene oxide-coated gold nanoparticles killed cells more rapidly than did noncoated or nonreduced graphene oxide-coated gold nanoparticles.

To unlock the full promise of messenger (mRNA) therapies, expanding the toolkit of lipid nanoparticles is paramount. However, a pivotal component of lipid nanoparticle development that remains a bottleneck is identifying new ionizable lipids. Here we describe an accelerated approach to discovering effective ionizable lipids for mRNA delivery that combines machine learning with advanced combinatorial chemistry tools. Starting from a simple four-component reaction platform, we create a chemically diverse library of 584 ionizable lipids. We screen the mRNA transfection potencies of lipid nanoparticles containing those lipids and use the data as a foundational dataset for training various machine learning models. We choose the best-performing model to probe an expansive virtual library of 40,000 lipids, synthesizing and experimentally evaluating the top 16 lipids flagged. We identify lipid 119-23, which outperforms established benchmark lipids in transfecting muscle and immune cells in several tissues. This approach facilitates the creation and evaluation of versatile ionizable lipid libraries, advancing the formulation of lipid nanoparticles for precise mRNA delivery. An approach combining machine learning and combinatorial chemistry enables the creation and evaluation of ionizable lipid libraries for lipid nanoparticle formulation to effectively deliver messenger RNA to several cells and tissues.

The medical risks of spaceflight are amplified as humans venture into longer-duration and greater-distance deep space voyages. During space missions, astronauts face the extremes of known health hazards, such as cosmic radiation and microgravity, as well as threats of the as-yet-unknown. For these missions to be productive and successful, ensuring the astronauts' safety and well-being is of foremost priority, and this could be achieved through innovations in space medicine. This Perspective explores the use of material technologies for delivery of space medicine in the context of health maintenance and preventive care, as well as treatment for non-emergency and emergency needs. We highlight innovative drug delivery systems, living pharmacies, regenerative medicine, and 3D printing and bioprinting approaches for health-care provision, and we share our vision on their potential applications in space. Finally, we discuss the benefits of space medicine research and its implications for advancing terrestrial health care. Space exploration amplifies medical risks to human health. Innovation in space medicine, drug delivery, regenerative medicine and 3D printing is key for astronaut health. This Perspective explores advanced material technologies for space health care and their applicability to terrestrial medicine.

Interdisciplinary strategies bridging oncology, neuroscience, bioelectronics and materials science will facilitate the development of next-generation therapies and devices for cancers of the central nervous system.

Transplanted cells can act as living drug factories capable of secreting therapeutic proteins in vivo, with applications in the treatment of Type 1 diabetes (T1D), blood borne disease, vision disorders, and degenerative neural disease, potentially representing functional cures for chronic conditions. However, attack from the host immune system represents a major challenge, requiring chronic immunosuppression to enable long-lived cell transplantation in vivo. Encapsulating cells in engineered biomaterials capable of excluding components of the host immune system while allowing for the transport of therapeutic proteins, oxygen, nutrients, metabolites, and waste products represents a potential solution. However, the foreign-body response can lead to isolation from native vasculature and hypoxia leading to cell death. In this prospective article, we highlight materials-based solutions to three important challenges in the field: (i) improving biocompatibility and reducing fibrosis; (ii) enhancing transport of secreted protein drugs and key nutrients and oxygen via engineered, semipermeable membranes; and (iii) improving oxygenation. These efforts draw on several disciplines in materials’ research, including polymer science, surfaces, membranes, biomaterials’ microfabrication, and flexible electronics. If successful, these efforts could lead to new therapies for chronic disease and are a rich space for both fundamental materials’ discovery and applied translational science.

Ionizable lipids are a key component of lipid nanoparticles, the leading nonviral messenger RNA delivery technology. Here, to advance the identification of ionizable lipids beyond current methods, which rely on experimental screening and/or rational design, we introduce lipid optimization using neural networks, a deep-learning strategy for ionizable lipid design. We created a dataset of >9,000 lipid nanoparticle activity measurements and used it to train a directed message-passing neural network for prediction of nucleic acid delivery with diverse lipid structures. Lipid optimization using neural networks predicted RNA delivery in vitro and in vivo and extrapolated to structures divergent from the training set. We evaluated 1.6 million lipids in silico and identified two structures, FO-32 and FO-35, with local mRNA delivery to the mouse muscle and nasal mucosa. FO-32 matched the state of the art for nebulized mRNA delivery to the mouse lung, and both FO-32 and FO-35 efficiently delivered mRNA to ferret lungs. Overall, this work shows the utility of deep learning for improving nanoparticle delivery.

In calcific aortic valve disease (CAVD), mechanosensitive valvular cells respond to fibrosis- and calcification-induced tissue stiffening, further driving pathophysiology. No pharmacotherapeutics are available to treat CAVD because of the paucity of (i) appropriate experimental models that recapitulate this complex environment and (ii) benchmarking novel engineered aortic valve (AV)–model performance. We established a biomaterial-based CAVD model mimicking the biomechanics of the human AV disease-prone fibrosa layer, three-dimensional (3D)–bioprinted into 96-well arrays. Liquid chromatography–tandem mass spectrometry analyses probed the cellular proteome and vesiculome to compare the 3D-bioprinted model versus traditional 2D monoculture, against human CAVD tissue. The 3D-bioprinted model highly recapitulated the CAVD cellular proteome (94% versus 70% of 2D proteins). Integration of cellular and vesicular datasets identified known and unknown proteins ubiquitous to AV calcification. This study explores how 2D versus 3D-bioengineered systems recapitulate unique aspects of human disease, positions multiomics as a technique for the evaluation of high throughput–based bioengineered model systems, and potentiates future drug discovery.

Triggerable coatings, such as pH-responsive polymethacrylate copolymers, can be used to protect the active pharmaceutical ingredients contained within oral solid dosage forms from the acidic gastric environment and to facilitate drug delivery directly to the intestine. However, gastrointestinal pH can be highly variable, which can reduce delivery efficiency when using pH-responsive drug delivery technologies. We hypothesized that biomaterials susceptible to proteolysis could be used in combination with other triggerable polymers to develop novel enteric coatings. Bioinformatic analysis suggested that silk fibroin is selectively degradable by enzymes in the small intestine, including chymotrypsin, but resilient to gastric pepsin. Based on the analysis, we developed a silk fibroin-polymethacrylate copolymer coating for oral dosage forms. In vitro and in vivo studies demonstrated that capsules coated with this novel silk fibroin formulation enable pancreatin-dependent drug release. We believe that this novel formulation and extensions thereof have the potential to produce more effective and personalized oral drug delivery systems for vulnerable populations including patients that have impaired and highly variable intestinal physiology.