Róbert Langer

Hydrogels that adhere to biological tissues and resist fibrosis are required to provide both optimal functionality and appropriate stiffness on diverse soft tissues to achieve therapeutic efficacy and biocompatibility. However, their performance is often limited by an intrinsic trade-off between functionality and stiffness. Through the incorporation of polymer brush coatings, we develop a modular hydrogel system to enable independent control of functionality and stiffness. By tailoring coating chemistry, coating thickness, and hydrogel network topology, we obtain consistent bioadhesion (~100 joules per square meter) and fibrosis suppression across the full stiffness range of soft tissues (1 kilopascal to 1 megapascal). Using this approach, we design a hydrogel that can maintain stable adhesion in vivo on a beating mouse heart and a hydrogel with no fibrotic capsule in immunocompetent mice over 40 days. This modular system offers a customizable approach for designing functional implants with tailored mechanical properties.

High-grade gliomas, including Glioblastoma (GBM), are the most common primary malignant tumor of the central nervous system and confer a dismal clinical prognosis. Current standard-of-care consists of maximal safe resection followed by radiation, chemotherapy, and/or tumor treating fields. Immunovirotherapy is a novel treatment modality in which oncolytic viruses (OVs) are engineered to induce oncolysis and concurrently stimulate an antitumor immune response. Presently, effective OV delivery is challenged by the complex tumor microenvironment and the blood-brain barrier. Hydrogels have shown promise in overcoming such challenges; built of natural and synthetic polymers, hydrogels can effectively deliver therapeutic payloads over an extended period. Hydrogels may also help facilitate OV augmentation with immune adjuvants such as checkpoint inhibitors. In this review, we 1) summarize advances and challenges in OV therapy; 2) describe how hydrogels can improve delivery of viral therapies; and 3) highlight opportunities for hydrogel-mediated OV–immune adjuvant combinations in the treatment of GBM and other high-grade brain tumors. Glioblastoma is an aggressive brain tumor with poor prognosis; while treated with surgery and therapy, immunovirotherapy faces delivery barriers that hydrogels may help overcome. Here, the authors summarize progress in oncolytic virus therapy, hydrogels for delivery, and their combination with immune therapies.

Ribonucleic acid (RNA)-based therapeutics have emerged as promising methods of disease treatment due to their ability to target the human genome and influence protein production, their versatility, and their relative lack of toxicity compared to other gene therapies. However, the RNA therapeutic design space is extremely large, encompassing multiple variables, including codon identities, secondary structure, and design of specific regions. RNA therapeutic optimization is difficult due to the impracticality of exploring such a vast design space experimentally. To address this limitation, deep learning methods have been employed to optimize RNA therapeutic development. In this review, we examine the application of deep learning models across three key aspects of RNA therapeutic development (RNA structure prediction, CRISPR activity, and RNA delivery), highlighting major contributions in these fields and analyzing how deep learning model architectures could affect model performance. We then discuss challenges associated with using deep learning for RNA therapeutics, such as computational and data limitations. Finally, we offer perspectives on areas for future exploration, such as emerging model architectures and methods of integration with more advanced high-throughput screening techniques. Ultimately, this review provides an overview of how deep learning is used in RNA therapeutic development and how it can evolve in the future.

Malnutrition can severely compromise immune function, rendering populations more vulnerable to both communicable and non-communicable diseases. Here, we discuss food fortification and micronutrient supplementation programs that have been instrumental in mitigating malnutrition across Africa and in controlling disease spread, marking considerable advances in public health throughout the continent. Jaklenec, Yang et al. examine how malnutrition heightens disease susceptibility in Africa. They comment on the successes of food-fortification efforts to date and outline remaining barriers and future directions.

The integration of artificial intelligence (AI) into cancer nanomedicine is transforming personalized therapy and diagnostics. Focusing on AI-guided design and optimization of nanomedicines, we evaluate how computational technologies can be used to improve targeting precision and therapeutic efficacy by matching treatments to each patient’s genetic and phenotypic profile. Surveying contemporary research, this Perspective presents a multidimensional view of AI-enabled nanomedicine that captures its technological, biological, and clinical complexity. Probabilistic and mechanistic models now facilitate the real-time adaptation of nanoparticle formulations. Looking ahead, we anticipate that AI will accelerate discovery and help nanomedicine realize its full potential in precision oncology. In addition to reviewing recent advances, we propose concrete guidelines for embedding AI throughout the nanomedicine pipeline, spanning data curation, model development, preclinical validation, and clinical translation. Finally, we highlight persistent gaps in standardized datasets, model interpretability, and regulatory alignment that must be addressed to achieve widespread clinical impact. Artificial intelligence is set to transform precision oncology by addressing challenges in targeting, efficacy, and therapeutic personalization. Its integration into cancer nanomedicine accelerates clinical translation by unifying technological, biological, and clinical complexities, enabling the design of nanoparticle therapies tailored to individual patient profiles.

Membranes that prevent cellular infiltration are essential components of immune-isolation devices. Stringent pore size control is critical to robustly exclude immune cells while preserving the efficient transport of nutrients and therapeutic molecules. Conventional membrane fabrication methods, however, struggle to balance these two properties. For instance, phase separation and fiber spinning generate highly tortuous pores that restrict diffusion, while random pore overlaps due to ion track etching result in oversized defects that compromise immune isolation. Here, we leverage scalable laser-writing tools to achieve spatially controlled open-through and dense pores with uniformly distributed submicrometer sizes for rapid transport and robust immune cell exclusion. Given the optical limits of laser aligners when fabricating submicrometer features, we tuned substrate reflectivity and exposure parameters to overcome these resolution limits. Self-standing and flexible membranes were achieved via thickness-tunable grid layers supporting membrane mechanical integrity. We report pore sizes as small as ca . 600 nm (below the resolution limits of the laser exposure systems) and over 20% open area at the exposure times of ∼3 min/cm 2 . Compared with conventional methods, this approach minimizes pore tortuosity, narrows the pore distribution, and improves the open pore density. Enhanced pore control is highlighted by macrophage infiltration studies, which indicate that these membranes reliably exclude macrophages at nominal pore sizes greater than those previously achievable. This approach thus provides a scalable pathway toward next-generation immunoisolation membranes for enhanced implantable therapeutic devices.

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.

Patient-specific, human-based cellular models integrating a biomimetic blood–brain barrier, immune, and myelinated neuron components are critically needed to enable accelerated, translationally relevant discovery of neurological disease mechanisms and interventions. To construct a human cell-based model that includes these features and all six major brain cell types needed to mimic disease and dissect pathological mechanisms, we have constructed, characterized, and utilized a multicellular integrated brain (miBrain) immuno-glial-neurovascular model by engineering a brain-inspired 3D hydrogel and identifying conditions to coculture these six brain cell types, all differentiated from patient induced pluripotent stem cells. miBrains recapitulate 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 glial fibrillary acidic protein. Unlike the coemergent fate specification of glia and neurons in other organoid approaches, 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.

Oral delivery of macromolecules is hindered by enzymatic degradation, poor epithelial permeability, and rapid gastric transit, leading to low bioavailability. Existing permeation enhancers (PEs), such as salcaprozate sodium and sodium caprate, improve absorption but do not fully address proteolytic degradation and require high doses due in part to short gastrointestinal residence times. We developed the Peroral Mucosal Epithelium Absorption Enhancer (PERMEATE) system, an orally administered polymer film designed to adhere to the small intestinal mucosa, maximizing contact between therapeutics, PEs, and the absorptive tissue. Utilizing Synthetic Tissue-Lining (SYNT™) technology, PERMEATE triggers endogenous catalase-dependent dopamine polymerization to form an in situ polydopamine coating, creating a temporary depot that enhances co-localization and prolongs exposure to the absorptive mucosa. We assessed PERMEATE’s potential to enhance the oral bioavailability of semaglutide (SEMA). High-throughput screening using the GI tissue robotic interface system (GI-ORIS) identified glycocholic acid (GCA) and ammonium carbonate (NHCO) as effective PEs when combined with SYNT. Ex vivo studies (n=8–24) and in vivo tests in Sprague-Dawley rats (n=5–11/group) demonstrated a 200-fold increase in bioavailability compared to SEMA alone (P=0.0001) and a 6-fold increase relative to SEMA+PE without SYNT (P=0.0011). In Yorkshire pigs (n=3–4), PERMEATE achieved a 2.4% absolute bioavailability, a 6-fold improvement over SEMA+PE controls (P=0.0316). These results suggest PERMEATE as a promising platform for improving oral macromolecule delivery through enhanced mucosal adhesion and prolonged therapeutic contact, supporting further development for clinical application.

Abstract Disclosure: P.D. Susilo: None. M. Kanelli: None. O. Petropulos: None. C. Dial: None. K. Kadasia: None. M. Buzo Mena: None. J. Liang: None. A. Hayward: None. K.A. Gaspie: None. S.M. Barron: None. R.R. Basani: None. A. Lopes: None. A. Yu: None. Introduction: Incretin peptide therapies have revolutionized obesity and diabetes treatment, yet overcoming oral delivery challenges—such as rapid gastrointestinal transit and limited intestinal absorption—is crucial to improving patient adherence, accessibility, and real-world effectiveness. To address these barriers, we developed the Peroral Mucosal Epithelium Absorption Enhancer (PERMEATE) method, which integrates synthetic tissue lining (SYNT) platform with proprietary permeation enhancers (PEs) to improve intestinal residence time and drive higher absorption. This proof-of-concept study demonstrates PERMEATE's ability to both create and significantly enhance the oral bioavailability of semaglutide (SEMA) in pig and rat models. Methods: A high-throughput ex vivo screen identified single and combination PEs with synergistic effects on SEMA permeation across porcine intestinal tissue. Ex vivo Franz experiments optimized formulation components and ratios to maximize colocalization of SEMA and PEs onto the intestinal tissue. Saline buffer washes were implemented to mimic a dynamic environment physiologically relevant to digestion. Lead formulations were tested in vivo in anesthetized Yorkshire pigs, a physiologically relevant gastrointestinal model, with plasma SEMA concentrations measured via LC-MS/MS over 168 hours. The area under the curve (AUC) was normalized by dose and compared to intravenous SEMA administration (n=4) to determine absolute bioavailability. To enhance replicates and rigor, formulations were also delivered via oral gavage to male rats (650-750 g, n=5-6 per group), with bioavailability assessed over 24 hours using the same methods. Results: Glycocholic acid (GCA) and ammonium carbonate (NHCO) were identified as the most effective PE combination with SEMA and SYNT, achieving a 15.5-fold increase in permeation compared to SEMA control in ex vivo tests. Optimized PERMEATE formulations improved colocalization of SEMA by 71.5-fold compared to a SEMA+PE control, after two washes, highlighting the ability of PERMEATE to create a localized depot and achieve prolonged residence time. In vivo, PERMEATE demonstrated a SEMA bioavailability of 2.4±1.6% in Yorkshire pigs (n=4), representing a significant 6-fold increase over the SEMA+PE control (0.4±0.3%, n=5; p=0.0316) and SEMA-Only control (0%, n=1). Improved bioavailability compared to controls was also observed in rats, highlighting translatability across multiple mammalian models. Conclusions: The PERMEATE platform, powered by SYNT™, significantly enhances the bioavailability of semaglutide (SEMA) in preclinical models, demonstrating up to a 6-fold improvement compared to controls. These findings underscore the potential of PERMEATE as a transformative platform for optimizing the oral delivery of macromolecule therapeutics. Presentation: Sunday, July 13, 2025

Abstract Disclosure: M. Hudson: Syntis Bio. L. Sandoval: Syntis Bio. P.D. Susilo: Syntis Bio. D. Sim: Syntis Bio. M. Buzo Pena: Syntis Bio. S. Pizzo: Syntis Bio. D. Ezekoye: None. A. Maheshwari: None. S. Cho: None. R. Sharma: None. M. Lanchantin: Syntis Bio. S. Zale: None. G. Traverso: Syntis Bio. R. Langer: Syntis Bio. R. Dhanda: Syntis Bio. V. Sethuraman: Syntis Bio. Background: SYNT-101 is a novel, orally administered therapeutic designed to treat obesity by establishing a tissue lining to redirect nutrient absorption past the proximal to the distal bowel. It has shown promising effects on glycemic control in multiple animal models and has demonstrated effective weight reduction and lean mass preservation in diet-induced obesity (DIO) rodent models. In this study, we present SYNT-101 first-in-human data, highlighting its safety, efficacy, and solid dosage form development. Methods: Nine healthy subjects (2 male, 7 female), aged 24 to 53 years with a BMI ranging from 19 to 29, received a single dose of SYNT-101 in a suspension formulation across multiple doses. The cohort was divided into three groups based on dosage: 25% (n=2), 50% (n=3), and 100% (n=4) of the target SYNT-101 level. Comprehensive safety assessments and oral glucose tolerance tests (OGTT) were performed to confirm SYNT-101 safety and efficacy. Endoscopic imaging was used to characterize duodenal surface coverage spatially and temporally. Plasma samples were collected to assess the impact on satiety/metabolic hormone levels (liver enzymes, leptin, ghrelin). Results: Endoscopic imaging revealed extensive SYNT-101 coverage throughout the duodenum. Safety assessments showed no adverse or serious adverse events in any treatment group. Per individual, liver enzymes, including aspartate transaminase (AST), alanine transaminase (ALT), and bilirubin, remained unchanged over a ten-day period post-treatment. Gastrointestinal tolerance was excellent, with no changes observed in the Gastrointestinal Symptom Rating Scale (GSRS) and an average pain rating of 0 (n=9). Histopathological examinations conducted 24 hours post-administration showed normal duodenal mucosa, with no signs of erosion or residual SYNT-101. OGTT tests demonstrated delayed glucose absorption with SYNT-101 treatment. After SYNT-101 administration, there was an average 34.7% reduction in the area under the curve within the first 30 minutes and a 20.9% reduction within 60 minutes, suggesting nutrient redirection from the duodenum to later in the intestine. Consistent with reduced food intake in the pre-clinical in vivo models, 100% of patients tested exhibited elevated plasma leptin levels and reduced ghrelin. Furthermore, we have shown enhanced coverage and reduced variability in OGTT by developing an orally delivered solid dosage formulation. Conclusions: SYNT-101 has demonstrated a strong profile of safety, tolerability, and efficacy in first-in-human studies, showing promise as a well-tolerated therapeutic option for effective weight loss solutions. Unlike many existing treatments, SYNT-101 offers a safe, tolerable, and effective oral alternative to current injectable and/or systemic therapies for weight management. Presentation: Sunday, July 13, 2025

Blood-brain barrier (BBB) dysfunction is an early feature of Alzheimer's disease (AD), yet the endothelial gene-regulatory programs involved remain incompletely understood. We integrate postmortem human single-nucleus transcriptomics with iPSC-based BBB models to define a conserved, inflammation-driven pathway that compromises barrier integrity. We identify an NF-κB-associated endothelial gene module endoM2 that is elevated in AD, inversely correlated with cognition, and enriched for inflammation and endothelial-to-mesenchymal transition signatures. Cytokine stimulation of iPSC-derived brain endothelial cells induces morphological remodeling, lipid accumulation, junctional disruption, and transcriptomic shifts that mirror endoM2. A targeted drug screen identifies the NF-κB inhibitor BAY11-7082 as protective against cytokine-induced changes. In our perfusable iPSC-derived BBB-Chip that recapitulates human BBB signatures, single-cell profiling reveals inflammatory endothelial state-specific programs reflecting those in AD brains and demonstrates that BAY11-7082 suppresses cytokine-triggered dysfunction and reverses inflammation-associated gene activation. Together, these findings position cerebrovascular inflammation as a therapeutic target to preserve BBB integrity in AD.

Welding is an essential process across various industries; however, it exposes workers to dangerous fumes, extreme heat and physical stress, which pose considerable health and safety hazards. To tackle these issues, this article introduces the creation of a remote-controlled human–robot welding system aimed at safeguarding workers while ensuring the quality of the welds. The system monitors a welder’s torch movements through a stereoscopic sensor and accurately reproduces them with a robotic arm, facilitating real-time remote welding. Operated by a student, it effectively welded standardized sheet metals in overhead positions while adhering to critical quality standards. The weld geometry met ISO 5817 requirements, tensile strength surpassed the base material specifications, and bending and hardness assessments verified the durability and integrity of the welds. When utilized in hazardous settings, the system showcases its capability to produce high-quality welds while significantly enhancing worker safety, underscoring its potential for real-world industrial applications.

Abstract Development and delivery of treatments for neurological diseases are limited by the tight and selective human blood–brain barrier (BBB). Although animal models have been important research and preclinical tools, the rodent BBB exhibits species differences and fails to capture the complexity of human genetics. Microphysiological systems incorporating human-derived cells hold great potential for modeling disease and therapeutic development, with advantages in screening throughput, real-time monitoring, and tunable genetic backgrounds when combined with induced pluripotent stem cell (iPSC) technology. Existing 3D BBB-on-chip systems have incorporated iPSC-derived endothelial cells but not the other major brain cell types from iPSCs, each of which contributes to brain physiology and disease. Here we developed a 3D Brain-Chip system incorporating endothelial cells, pericytes, astrocytes, neurons, microglia, and oligodendroglia from iPSCs. To enable this multicellular 3D co-culture in-chip, we designed a GelChip microfluidic platform using a 3D printing-based approach and dextran-based engineered hydrogel. Leveraging this platform, we co-cultured and characterized iPSC-derived brain-on-chips and modeled the brain microvasculature of APOE4 , the strongest known genetic risk factor for sporadic Alzheimer’s disease. These 3D brain-on-chips provide a versatile system to assess BBB vascular morphology and function, investigate downstream neurological effects in disease, and screen therapeutics to optimize delivery to the brain. Significance Statement The blood–brain barrier (BBB) is both a contributing factor to neurological disease and a major obstacle to its treatment, yet human-relevant models remain limited. Most existing brain-on-chip systems incorporate only subsets of BBB cell types and cannot capture the full cellular complexity of the human neurovascular unit. Here, we establish a vascular-perfusable 3D Brain-Chip using human induced pluripotent stem cell-derived brain cells including endothelial cells, pericytes, astrocytes, neurons, microglia, and oligodendroglia. This system enables systematic analysis of human genetic risk factors, such as APOE4 in Alzheimer’s disease, and provides a powerful platform to investigate BBB function and dysfunction and accelerate the development of more effective neurological therapies.

Prime editors make programmed genome modifications by writing new sequences into extensions of nicked DNA 3′ ends1. These edited 3′ new strands must displace competing 5′ strands to install edits, yet a bias towards retaining the competing 5′ strands hinders efficiency and can cause indel errors2. Here we discover that nicked end degradation, consistent with competing 5′ strand destabilization, can be promoted by Cas9-nickase mutations that relax nick positioning. We exploit this mechanism to engineer efficient prime editors with strikingly low indel errors. Combining this error-suppressing strategy with the latest efficiency-boosting architecture, we design a next-generation prime editor (vPE). Compared with previous editors, vPE features comparable efficiency yet up to 60-fold lower indel errors, enabling edit:indel ratios as high as 543:1. Engineered prime editor systems with reduced occurrences of unwanted insertions or deletions during genome editing are developed.

Abstract The intersection of biotechnology and materials science has driven medical and scientific innovation for decades and is poised to make similar transformative impacts over the next 50 years. Advanced drug delivery systems, including nanoparticles and larger delivery material platforms, are enhancing therapeutic precision, while tissue engineering and regenerative medicine are laying the groundwork for bioprinting complex organs, offering new possibilities for transplantation and repair. Nanotechnology and biomedical devices are reshaping diagnostics and therapeutics, enabling real-time monitoring essential for personalized health care. Additionally, emerging fields such as space biotechnology and machine learning-driven biomaterials design hold potential for cutting-edge discoveries. This article examines the historical trajectory, current state-of-the-art applications, and bold future directions of biotechnology in materials science, emphasizing its impact on human health and its untapped potential yet to be explored. Graphical abstract

Gastrointestinal (GI) dysmotility and associated conditions affect over 20% of population, yet pharmacological, behavioural, and surgical interventions offer limited therapeutic efficacy. Targeted electrical stimulation addressing underlying neuromuscular pathology stands to transform our ability to treat dysmotility. Here, we developed a closed-loop GI neuroprosthesis which activates or relaxes GI tract musculature through electrochemical stimulation in response to sensed food stimuli. We additionally describe a tool supporting minimally invasive endoscopically guided implantation that can penetrate the mucosa, accurately localize the submucosa, and safely deploy this device to directly interface with the enteric nervous system. The neuroprosthesis enables generation of coordinated peristaltic waves, significantly increasing the motility rate in a swine model of oesophageal and stomach dysmotility (p < 0.05, student’s t-test). Further, by directly modulating the myenteric plexus and thus mimicking meal ingestion, we induce peristalsis in a fasted state and achieve a metabolic response commensurate with a fed or satiated state. This neuroprosthesis and implantation platform expand opportunities in fundamental studies and treatments of metabolic and neuromuscular pathologies affecting the GI tract. Gastrointestinal motility disorders affect over 20% of the population, yet current therapies provide limited relief. Here, the authors show that in a swine model a closed-loop GI neuroprosthesis restores peristalsis and enhances metabolic responses via targeted electrical and chemical stimulation

ANCA-vasculitis (AAV) is a small-vessel vasculitis characterized by the presence of autoantibodies against proteinase-3 (PR3) or myeloperoxidase (MPO). The dynamics of the T-cell response within tissues is studied best in animal models. It was the aim to analyze the lesional T-cell dynamics in the experimental autoimmune vasculitis model. Female Wistar Kyoto-rats were immunized with human MPO emulsified in complete Freund's adjuvant. Control animals received complete Freund's adjuvant without MPO. Selected groups received anti-IL17A treatment. Lesional T-cells from kidneys were assessed by flow cytometry (FACS), realtime polymerase chain reaction (PCR) and EliSpot. All animals immunized with MPO developed signs of vasculitis. At week six, lung damage expressed as petechial bleeding score and renal damage quantified by albuminuria were highest. As analyzed by FACS, the fraction of renal Th17 cells peaked at week six in MPO rats equaling the proportion of Th1 cells. MPO-specific renal Th1 and Th17 cells were detectable by EliSpot at weeks four and six post-immunization in MPO-immunized rats being absent in control rats. Neutralization of IL-17A did not affect the development of humoral and cellular anti-MPO immunity. Likewise, pulmonary and renal vasculitis were not ameliorated. In summary, the dynamics of the lesional T-cell response in the EAV model shows a major participation of MPO-specific Th17 and Th1 cells in renal vasculitis. Simple cytokine neutralization was not efficacious in this disease model so that combined neutralization approaches should be studied further.

ABSTRACT Iron deficiency anemia (IDA) is a persistent global health challenge, particularly in low‐ and middle‐income countries, necessitating effective iron fortification strategies. In this study, we developed FeC‐4‐1, a novel iron complex composed of ferrous sulfate, vitamin C (VC), and histidine, to enhance iron stability, cellular iron uptake, and compatibility with food matrices. FeC‐4‐1 exhibited high stability across a broad pH range (3–12). Under simulated gastric conditions, FeC‐4‐1 released nearly 100% of its iron and VC within 10 min, ensuring efficient cellular iron uptake. FeC‐4‐1 also demonstrated superior oxidation resistance compared to FeSO 4 , exhibiting 2.5‐fold lower color change in polyphenol‐rich banana milk after 2‐h treatment. Long‐term storage studies revealed that FeC‐4‐1 maintained 60% of its initial total iron content with the ferrous iron fraction remaining at ∼80% after 12 months, indicating minimal oxidation over time. Bioaccessibility studies following an established INFOGEST protocol showed that FeC‐4‐1 provided about 2‐fold higher bioaccessible iron compared to FeSO 4 under room temperature conditions. In addition, FeC‐4‐1 resulted in approximately a 3.2‐fold increase in total intracellular iron compared to FeSO 4 in Caco‐2 cells. Sensory evaluation results demonstrated that FeC‐4‐1 fortification at 16 mg per serving (50% RDA of iron) in bouillon soup did not alter flavor or mouthfeel. These findings suggest that FeC‐4‐1 is a technically feasible and effective iron fortificant, offering enhanced stability, bioaccessibility, and consumer acceptability for in‐home iron fortification.

Rapidly administered emergency drug therapy represents life-saving treatment for a range of acute conditions including hypoglycaemia, anaphylaxis and cardiac arrest. Devices that automate emergency delivery, such as pumps and automated injectors, are limited by the low stability of liquid formulations. In contrast, dry particulate formulations of these drugs are stable but are incompatible with drug pumps and require reconstitution before administration. Here we develop a miniaturized (<3 cm3), lightweight (<2 g), minimally invasive, fully wireless emergency rescue device for the storage and active burst-release of indefinitely stable particulate forms of peptide and hormone drugs into subcutaneous sites for direct reconstitution in interstitial biofluids and rapid (<5 min) therapeutic effect. Importantly, the device delivers drug across fibrotic tissue, which commonly accumulates following in vivo implantation, thereby accelerating systemic delivery. Fully wireless delivery of dry particulate glucagon in vivo is demonstrated, providing emergency hypoglycaemic rescue in diabetic mice. In addition, triggered delivery of epinephrine is demonstrated in vivo. This work provides a platform for the long-term in vivo closed-loop delivery of emergency rescue drugs. A wireless, minimally invasive emergency rescue device is developed for the active burst-release of stable particulate forms of peptide and hormone drugs into subcutaneous sites in mice.

Purpose: Subpectoral biceps tenodesis is a widely used surgical technique to relieve pain and restore function in the shoulder by securing the long head of the biceps tendon. This study aimed to evaluate the mechanical performance of three fixation techniques using cortical button, interference screw and keyhole methods by assessing their strength, durability and strain distribution, incorporating the novel application of digital image correlation (DIC). Methods: Thirty fresh porcine bone-tendon specimens were allocated evenly among the fixation techniques. Biomechanical testing involved cyclic axial loading (10-100 N) for 500 cycles, followed by load-to-failure testing using a universal testing machine. DIC analysis assessed strain distribution around the bone drill site. Statistical comparisons of displacement, load-to-failure and strain patterns were performed. Results: Cortical button fixation demonstrated the highest average load-to-failure at 353 ± 45 N, with all specimens completing 500 cycles and showing the least variability. In comparison, interference screw fixation had the lowest average load-to-failure (271 ± 71 N) with two failures occurring before 500 cycles, and the keyhole technique showed intermediate performance at 319 ± 45 N, also with two early failures. Cyclic displacement after 500 cycles was lowest for the interference screw (3.16 ± 0.52 mm), followed by the keyhole (11.51 ± 2.08 mm), and highest for the cortical button (13.84 ± 1.90 mm). Displacement range after 500 cycles was also lowest in the interference screw group (0.62 ± 0.05 mm), compared to the cortical button (0.88 ± 0.07 mm) and keyhole (0.91 ± 0.23 mm). DIC revealed the highest maximum first principal strain around cortical button fixation (0.21%), followed by interference screw (0.16%) and keyhole (0.13%). Conclusion: Cortical button fixation demonstrated the highest load-to-failure and the lowest variability, indicating mechanical reliability. The interference screw and keyhole techniques showed comparable load-to-failure values and cyclic displacement but exhibited greater variability. DIC analysis revealed higher localized strain around the cortical button fixation, whereas the interference screw and keyhole techniques displayed more evenly distributed strain. Level of Evidence: Level V.

We propose the nasal administration of calcium-enriched physiological salts as a new hygienic intervention with possible therapeutic application as a response to the rapid and tenacious spread of COVID-19. We test the effectiveness of these salts against viral and bacterial pathogens in animals and humans. We find that aerosol administration of these salts to the airways diminishes the exhalation of the small particles that face masks fail to filter and, in the case of an influenza swine model, completely block airborne transmission of disease. In a study of 10 human volunteers (5 less than 65&nbsp;years and 5 older than 65&nbsp;years), we show that delivery of a nasal saline comprising calcium and sodium salts quickly (within 15&nbsp;min) and durably (up to at least 6&nbsp;h) diminishes exhaled particles from the human airways. Being predominantly smaller than 1&nbsp;&mu;m, these particles are below the size effectively filtered by conventional masks. The suppression of exhaled droplets by the nasal delivery of calcium-rich saline with aerosol droplet size of around 10&nbsp;&mu;m suggests the upper airways as a primary source of bioaerosol generation. The suppression effect is especially pronounced (99%) among those who exhale large numbers of particles. In our study, we found this high-particle exhalation group to correlate with advanced age. We argue for a new hygienic practice of nasal cleansing by a calcium-rich saline aerosol, to complement the washing of hands with ordinary soap, use of a face mask, and social distancing.

In the version of the article initially published, a thiophene ring in Fig. 1a was incorrectly drawn and has now been amended in the HTML and PDF versions of the article, as seen below:

Oral delivery is the most preferred route for nutraceuticals due to its convenience and high patient compliance. However, bioavailability is often compromised by poor solubility, instability, and first-pass metabolism in the gastrointestinal tract. This review examines current and emerging oral delivery platforms designed to overcome these barriers and enhance nutraceutical efficacy. Traditional carriers-proteins, lipids, and carbohydrates-highlighting their delivery mechanisms and limitations, are first explored. Advancements in material science have led to novel platforms such as biodegradable polymers, metal-organic frameworks (MOFs), metal-polyphenol networks (MPNs), and 3D printing technologies. Biodegradable polymers improve stability and enable controlled release of bioactives. MOFs offer high surface area and tunable porosity for encapsulating and protecting sensitive compounds. MPNs provide biocompatible, stimuli-responsive systems for targeted nutrient delivery. Meanwhile, 3D printing facilitates the fabrication of personalized delivery systems with precise control over composition and release kinetics, especially when integrated with artificial intelligence (AI) for precision nutrition. By comparing traditional and next-generation strategies, this review outlines key design principles for optimizing oral delivery systems. The transformative potential of these innovations is underscored to improve the bioavailability and therapeutic outcomes of nutraceuticals, ultimately advancing personalized and targeted nutrition solutions.

Transistor miniaturization has for a long period of time enabled the so-called ‘happy scaling era'. Scaling devices made them faster, cheaper and more energy efficient. Despite a slowdown of this trend in the 2000s, the introduction of strained channels, high-k / metal gates and non-planar field-effect transistors successfully extended the famous Moore's law. In the meantime, parasitic contributions from access resistances became important performance detractors [1]. Active doping concentrations in SiGe:B and Si:P epitaxial layers, typically used as source/drain (S/D) materials in PMOS and NMOS transistors, respectively, should hence be maximized to reduce contact resistivities (p<inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">c</inf>) [2]. Engineering the band structures in the contact regions and identifying suitable contact metals and silicides, enabling advantageous replacements of Ti silicides, are other subjects of intense research efforts.

Biomaterials NeoCast is a shear-thinning, solvent-free, non-adhesive liquid embolic. When injected into vasculature, shear forces disrupt particle interactions and drive NeoCast into the distal vessels (top vessel). As the vessels fill and shear reduces, the particle interactions resume; the material coalesces and fills the proximal vessels (middle vessel). NeoCast then crosslinks into a solid elastomer, ensuring durable occlusion (bottom vessel). More details can be found in article 2404011 by Upma Sharma and co-workers.

Abstract Reversible contraceptives empower women to prevent unintended pregnancies and enable family planning. However, the need for frequent dosing with pills or injections often leads to suboptimal medication adherence and reduced effectiveness–an issue common to many chronic conditions. Long-acting drug delivery implants offer a compelling alternative by enabling autonomous, multi-year drug release, thereby improving real-world adherence and treatment outcomes. However, user acceptability and access are limited by need for invasive insertion and surgical end-of-life removal, particularly in low-resource settings, as well as by limited drug loading and suboptimal drug utilization efficiency, which constrain both the duration of therapy and the range of drugs that can be effectively delivered. To address these limitations, we developed the Monolithic Shape-shifting Absorbable Implants for Chronic Care (MoSAIC) platform–a minimally invasive, fully bioresorbable system that integrates compacted drug formulations with a space-efficient device architecture. This approach reduces implant size, eliminates the need for surgical removal, and prolongs therapeutic duration compared to existing implants. We develop compacted formulations of the contraceptive drug levonorgestrel (LNG), and other poorly water-solubility drugs, demonstrating exceptional drug loading (100% w/w) and multi-year sustained drug release via surface-mediated dissolution in rats. When incorporated into MoSAIC devices, these formulations enable high-efficiency drug loading and zero-order drug release kinetics with geometrically tunable rates and durations. As a result, MoSAIC systems can be designed to be smaller, less invasive, and/or longer lasting than current contraceptive implants such as Jadelle® and Nexplanon®. The MoSAIC platform expands access to reversible contraception and supports long-term medication adherence, with the potential to improve health outcomes and quality of life. More broadly, it provides a flexible approach for delivering other potent, low-solubility therapeutics and lays the foundation for a “dose it and forget it” paradigm in chronic disease management, where adherence is designed into the therapy itself.

Lipid nanoparticle RNA (LNP-RNA) formulations are used for the delivery of vaccines and other therapies. RNA molecules are encapsulated within their interior through electrostatic interactions with positively charged lipids. The identity of the lipids that present at their surface play a role in how they interact with and are perceived by the body and their resultant potency. Here, we use a model formulation to develop cryogenic sample preparation for molecular depth profiling Orbitrap secondary ion mass spectrometry (Cryo-OrbiSIMS) preceded by morphological characterisation using cryogenic transmission electron microscopy (Cryo-TEM). It is found that the depth distribution of individual lipid components is revealed relative to the surface and the RNA cargo defining the core. A preferential lipid orientation can be determined for the 1,2-Dimyristoyl-glycero-3-methox-polyethylene glycol 2000 (DMG-PEG2k) molecule, by comparing the profiles of PEG to DMG fragments. PEG fragments are found immediately during analysis of the LNP surface, while the DMG fragments are deeper, coincident with RNA ions located in the core, in agreement with established models of LNPs. This laboratory-based de novo analysis technique requires no labelling, providing advantages over large facility neutron scattering characterisation.

The development of novel therapies for central nervous system (CNS) diseases, particularly neurodegenerative disorders like Alzheimer's disease (AD), is a critical global health priority. Biotherapeutics, such as monoclonal antibodies (mAbs) and RNA-based therapies, have shown potential for treating brain disorders. However, their clinical progress is limited by their difficult access to their brain targets. At the preclinical level, nanotechnology has been shown, to help these molecules overcome the biological barriers that imped their adequate brain delivery. This review highlights advances in this area and the challenges for the translation to the clinic. Key nanotechnology-based strategies, such as surface modifications utilizing endogenous protein corona, functionalization with targeting ligands, therapeutic ultrasound-mediated microbubble oscillation were particularly analyzed. Additionally, in line with the focus of the Special Issue, this review integrates the concept of chronotherapy, with a focus on AD treatment, highlighting the idea that, by aligning nanoparticle (NP)-based drug delivery with circadian rhythms, it may be possible to improve therapeutic outcomes. Finally, the article analyzes current strategies in CNS drug delivery in clinical trials and provides future directions within this frame, notably in the area of AD.

Vaccination remains a critical tool in preventing infectious diseases, yet its effectiveness is undermined by under-immunization, particularly for vaccines requiring multiple doses that patients fail to complete. To address this challenge, the development of single-injection platforms delivering self-boosting vaccines has gained significant attention. Despite some advances, translating these platforms into clinical applications has been limited. In this study, a novel polyanhydride-based polymeric delivery platform is introduced, designed for single-injection self-boosting vaccines, replacing multiple doses. Over 20 polyanhydride polymers are synthesized and screened, ultimately down selecting to 6 for in vitro studies, and 2 for in vivo studies. Using diphtheria toxoid (DT) as a model antigen, programmed pulsatile release with a narrow window is demonstrated, ideal for self-boosting immunization. The platform effectively protects the pH-sensitive antigen before release, achieving recovery rate of 39.7% to 89.7%. The system's tunability is further enhanced by machine learning algorithms, which accurately predict release profiles, confirmed through experimental validation. In vivo studies in a mouse model reveals that the platform induces DT-specific antibody responses comparable to those generated by traditional multi-dose regimens. Collectively, these findings highlight the potential of this platform to deliver various vaccines, offering a potentially promising solution to the global challenge of under-immunization.

Structural nanomedicines are engineered constructs that arrange therapeutic components into well-defined architectures to maximize efficacy. Their multivalent, multifunctional design offers key advantages over unstructured formulations, including targeted delivery, expanded therapeutic windows, and enhanced target engagement. The mRNA COVID-19 vaccines exemplify their transformative potential. However, structural precision varies, and more well-defined architectures will streamline optimization, manufacturing, and regulation. Unlike small molecule drugs, nanomedicines within a batch are not identical. Identifying the most effective, least toxic structures will advance our understanding of structure-function relationships and therapeutic mechanisms. This work highlights structural nanomedicines─small molecules, nucleic acids, and biologics─to galvanize the field and drive innovation toward even safer, more effective treatments that benefit patients.

Rotator cuff injuries are a common cause of shoulder pain, primarily affecting individuals older than 40 years, with the incidence increasing progressively with age. Advancements in surgical techniques have led to the development of arthroscopic techniques. This evolution has transitioned through various arthroscopic suture anchor rotator cuff repair configurations, including single-row, double-row, and transosseous-equivalent constructs. Although these innovations have replicated the biomechanics of the original transosseous technique conducted using an open approach, they often require multiple anchors, significantly increasing surgical costs. Additionally, anchor-related complications persist. To enhance the feasibility and affordability of implant-free transosseous repair, a reusable instrumentation system, was developed by Drillbone (Brno, Czechia). This innovative device facilitates robust and reproducible transosseous rotator cuff repairs while substantially reducing procedural costs. We present a surgical technique using bone tunneling device, showing its application in arthroscopic rotator cuff repair.