Giovanni Traverso

Abstract Ingestible electronic systems offer a minimally invasive means to continuously monitor core body temperature, providing critical insights into a range of health conditions. However, the size of ingestible sensors often limits their use, particularly in paediatric populations. Here we report a miniaturized ingestible temperature sensor for continuous internal monitoring. The device integrates a 1 mm × 1 mm low-power (10 nW) integrated circuit, a 5 mm × 5 mm antenna for wireless backscatter communication and a coin-cell battery. The fully encapsulated system measures just 6 mm in diameter and 4 mm in height, dimensions aligned with those of US Food and Drug Administration-approved osmotic controlled-release oral delivery system and smaller than video capsule endoscopy devices, thus minimizing the risk of gastrointestinal retention. We evaluate the sensor in swine models under diverse physiological and pathophysiological conditions. This includes use in ambulatory multi-day monitoring, scenarios with inflammation-induced altered gastrointestinal transit and deployment alongside intravascular devices for vascular navigation and guidance.

Drug delivery to the oesophagus poses unique challenges, including rapid transit time due to gravity and the presence of a stratified squamous non-keratinized epithelium. Here, to rapidly identify formulations of excipients for enhanced drug delivery to the oesophagus, we developed an oesophageal tissue screening system consisting of specialized custom plates, to incorporate gravity effects, and excised oesophageal mucosa tissues. Using the screening system, we built an excipient library identifying the most effective non-toxic permeation enhancers and selected the formulation that could prolong the retention on the oesophageal mucosa. We identified an absorption enhancer that resulted in a 876-fold increase in the oesophageal transport of a model drug (4 kDa) in pig tissue. We validated this formulation in human oesophageal tissue and in vivo in pigs with the model drug and infliximab (149 kDa), demonstrating enhanced permeability. We characterized the mechanism of the approach, noting its capacity for enhanced delivery without causing cellular disruption of the oesophageal tissue. The oesophageal tissue screening system shows promise for high-throughput screening of effective oesophageal drug delivery systems.

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.

Abstract Insulin therapy revolutionized the care of patients with diabetes starting ∼100 years ago, yet insulin-induced hypoglycemia remains a serious life-threatening complication of insulin therapy. Glucagon is a highly effective treatment; however current dosage forms remain under-utilized due to poor patient compliance. The development of improved and situation-specific glucagon therapies remains challenging due to the poor drug stability and incomplete knowledge of the kinetics of different hypoglycemic events. Thus, we analyzed continuous glucose monitor (CGM) data from 1135 patients with type 1 diabetes (T1D) representing 246.18 patient years. We show that a surprisingly large proportion of hypoglycemic episodes (20-30%) are follow-on events resulting from under-treatment of prior events, and that the average duration of independent hypoglycemic events can last up to 79 to 108 minutes. We further show that the kinetics of hypoglycemic onset and persistence varies significantly by patient history, severity, time of occurrence. Guided by these findings, we recognize the opportunity to develop high-density, readily-soluble, and thermostable (ReST) solid glucagon formulations, and painless application-specific microneedle-patches that are in line with the timing needs of T1D patients who are awake and asleep. Thus, we demonstrate (1) on-demand patches for rapid prevention or treatment of mild hypoglycemia during the day, and (2) enzyme-driven hypoglycemia-responsive patches supporting autonomous glucagon release during the night. We show excellent in vitro glucagon stability, loading, and release kinetics of both systems and demonstrate their ability to treat hypoglycemia in diabetic animals. The engineering of these delivery systems demonstrates the potential of human CGM data and solid glucagon formulations to enable new modes of glucagon therapy, thereby expanding the clinical role of glucagon beyond the emergency setting.

Type 1 Diabetes (T1D) is a devastating disease in which the immune system attacks insulin- producing beta cells in the pancreas, disrupting the normal blood glucose regulation mechanism and resulting in the significant burden of ongoing blood glucose monitoring and management and longer-term damage to organs and tissues. An emerging therapy for T1D includes transplanting insulin-producing stem cell (SC)-derived aggregates into patients, restoring normal regulation of blood glucose and eliminating the need for insulin injections. To enable stable storage, distribution, and clinical administration of this therapeutic, reliable cryopreservation methods are required. However, current cryopreservation protocols result in low cell viability post thaw and have challenges in scalability. This review provides background on stem cell therapy for T1D and the production and storage pipeline of these SC-derived aggregates, with a focus on the challenges of cryopreservation. We review the fundamental physics involved in cryopreservation, including cryoprotective agents (CPAs), CPA loading and unloading, the importance of cooling and rewarming rate selection, and why the cell aggregate microstructure of islets presents a particularly difficult challenge for cryopreservation. Finally, we highlight important developments in SC-derived aggregate cryopreservation and the state of the art.

Large animal models, while valuable, are expensive, time-consuming, and limited to discrete interventional or terminal timepoints, while existing benchtop models do not offer an accurate representation of the esophageal environment. Moreover, current pre-clinical models cannot effectively simulate swallowing dysfunction (dysphagia), restricting progress in understanding motility disorders like achalasia and hindering evidence-based dietary recommendations. In response, we present RoboGullet, a biomimetic soft-robotic model with independent localized longitudinal and circumferential muscle actuation, enabling, for the first time, simulation of both normal and diseased esophageal motility. We further enhance realism with a biohybrid variant, RoboGullet + , incorporating porcine esophageal mucosa/submucosa. We demonstrate this platform's versatility through three key applications: assessing stent migration, simulating achalasia I-III within clinical diagnostic criteria, and analyzing bolus swallowing. Our findings reveal that: (1) stent migration increases over fivefold when incorporating longitudinal muscle movement versus isolated circumferential; (2) using a viscous non-Newtonian bolus improves high-resolution manometry diagnostic sensitivity of Achalasia III through increasing the Distal Latency diagnostic metric by 20.83%; and (3) stirring Greek-style yoghurt (common non-Newtonian dietary recommendation) significantly improves bolus transit versus unstirred for Achalasia Types I-II patients. This establishes RoboGullet+ as a powerful translational tool, advancing our understanding of esophageal motility and its therapeutic interventions.

The rapid growth of personalized medicine has driven increased demand for battery-free, energy-efficient ingestible electronics for on-demand gastrointestinal (GI) drug delivery. This article presents the first fully-integrated, battery-free ingestible CMOS platform that harvests energy from a galvanic cell (GC) through a reconfigurable switched-capacitor converter, with pH-adaptive maximum power point tracking (MPPT) guided by on-chip gastric pH measurement. The system offers three clinically relevant drug-delivery modes, selectable via 13.56 MHz wireless RF commands: burst, low-energy dissolve, and balanced modes. Upon receiving a drug-delivery command, the system applies an optimal voltage bias according to the measured pH and selected delivery mode, to electrochemically dissolve a metal membrane and release the payload. Fabricated in a 65-nm CMOS, the 6-mm<sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sup> chip integrates with a drug-delivery chamber, GC, and off-chip antenna to form a capsule that fits within the dimensions of commercial ingestible electronics. Ex vivo and in vitro tests demonstrate reliable system operation, with a 6-cm RF detection range from the tissue surface, 0.32-pH sensor resolution, and 72% end-to-end energy-harvesting efficiency with a wide range of input powers from 30 to <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> <tex-math notation="LaTeX">$200~\mu $</tex-math> </inline-formula>W. By integrating pH-adaptive MPPT with RF-controlled multimode drug release on a single platform, this work advances adaptable, responsive, and patient-specific therapies for GI drug delivery.

Medication non-adherence remains a critical healthcare challenge, contributing to approximately 125,000 preventable deaths each year and incurring over $100 billion in annual costs in the United States. Current adherence assessment strategies are constrained by limited scalability, suboptimal patient acceptability, and environmental sustainability concerns. To address these limitations, we developed SAFARI (Smart Adherence via FARaday cage And Resorbable Ingestible), a bioresorbable, passive RFID system that enables precise monitoring of medication ingestion events. The platform incorporates a novel cellulose–metal particle–based radiofrequency (RF) shielding layer, effectively creating a Faraday cage that facilitates reliable signal detection. By employing fully biodegradable materials, SAFARI obviates the need for device retrieval or battery replacement, thereby mitigating electronic waste. Moreover, the tags are compatible with standard gelatin or hydroxypropyl methylcellulose (HPMC) capsules, further enhancing clinical translational potential. In vivo evaluation in swine models corroborated SAFARI’s ability to accurately detect ingestion events while demonstrating complete biodegradation following administration. These findings highlight the system’s potential to improve patient adherence tracking without introducing significant logistical burdens or ecological impact. As such, SAFARI establishes a foundational framework for the development of next-generation, eco-conscious adherence monitoring solutions and associated interventions—ultimately aiming to bolster therapeutic outcomes and reduce healthcare expenditures. Medication non-adherence represents a healthcare challenge, generating over $100 billion in additional costs annually in the USA. Here, the authors developed a resorbable and ingestible system designed for assessing medication adherence. Figure 1. Schematic illustration of capsule based, biodegradable medication adherence tracking system with envisioned scenario for clinical use. A, Bio-RFID capsule administration. B, Shielding coating dissolution and payload release C, Monitoring of the Tag ID and frequency range, recording of the payload for tracking adherence. D, Dissolution and biosorption of the coating, tag and the capsule.

Oral drug delivery is a widely used method of drug administration; however, achieving localized drug release at specific regions of the gastrointestinal (GI) tract is generally accomplished by using broad environmental differences. The GI tract is a complex system with regional differences in composition, such as selective expression of mucin glycoproteins in different organs. Here, we identify small molecule ligands that can selectively bind to the different mucins to localize drug delivery to the small intestine and stomach. We demonstrate up to a 10-fold increase in particle binding to these organs and up to a 4-fold increase in selectivity compared to chitosan. Additionally, we observe up to a 9-fold increase in budesonide concentration in the small intestine and a 25-fold increase in tetracycline concentration in the stomach. These results show that we have developed a versatile platform capable of sequestering a variety of drugs in certain GI tract organs.

While treatment remains essential, disease prevention often proves more effective in improving outcomes, enhancing well-being and reducing healthcare costs. Despite this understanding, preventative medical practices are still underutilized. Continuous monitoring technologies can help to address this gap by enabling early symptom detection, tracking disease recurrence and assessing treatment responses, yet few of the technologies have been integrated into clinical practice. In this Review, we discuss notable advances in continuous monitoring and the barriers to their translation. We focus on technologies that enable either continuous measurement for at least one week or periodic measurements for at least one month, including remotely interfacing technologies, wearables and other directly interfacing systems, and internally interfacing implanted devices. Continuous monitoring improves disease-risk assessment, tracks disease progression and enhances overall health management. However, broader and more reliable datasets from diverse clinical trials, alongside supportive policies and financial incentives, will be essential to overcoming translational barriers and to integrating these technologies into healthcare. This Review discusses how continuous monitoring technologies can enable early symptom detection, disease recurrence tracking and treatment response assessment, and how these technologies are being integrated into clinical practice.

Ovarian cancer is one of the most lethal gynecological malignancies, with high mortality rates primarily due to late-stage diagnoses and extensive peritoneal metastases. Despite improvements in surgical and chemotherapeutic treatments, the prognosis for advanced ovarian cancer remains poor, highlighting the urgent need for innovative therapeutic approaches. Hyperthermic intraperitoneal chemotherapy (HIPEC) has emerged as a promising treatment, delivering heated chemotherapeutic agents directly into the peritoneal cavity post-cytoreductive surgery. However, HIPEC adoption is limited by three critical complications: suboptimal therapeutic efficacy in resistant tumors; abdominal adhesion formation; and systemic toxicity, including cisplatin-induced nephrotoxicity. This study investigates carbon monoxide gas- entrapping materials (CO-GEMs) as a novel multifunctional adjunctive therapy to address the three HIPEC limitations simultaneously. CO-GEMs effectively encapsulate and deliver carbon monoxide, leveraging the differential effects of CO in cancerous where it has been shown to reduce tumor burden. In ovarian cancer models, CO-GEMs significantly enhanced cisplatin efficacy, reducing the metastatic tumor burden by 46.6% through the downregulation of drug resistance pathways, including the IL-17, TNF, and NF-κB pathways; ECM receptor interaction, and VEGF signaling. CO-GEMs also prevented peritoneal adhesion formation by suppressing inflammatory cell infiltration and collagen deposition, with a significant reduction in adhesion severity scores. Additionally, enteral CO-GEMs provided significant nephroprotection against cisplatin-induced acute kidney injury, as demonstrated by reduced blood urea nitrogen levels. CO-GEMs represent a promising innovation that simultaneously improves HIPEC therapeutic efficacy, prevents surgical complications, and reduces systemic toxicity. This multifunctional approach addresses multiple clinical limitations of HIPEC, potentially transforming treatment outcomes for patients with advanced ovarian cancer through an enhanced therapeutic index and improved safety profile.

Acute mesenteric ischemia (AMI) results from insufficient blood flow to the intestines, leading to tissue necrosis with high morbidity and mortality. Diagnosis is often delayed because of nonspecific symptoms that mimic common gastrointestinal conditions. Current diagnostic methods, such as computed tomography and mesenteric angiography, are complex, costly, and invasive, highlighting the need for a rapid, accessible, and minimally invasive alternative. Here, we present FIREFLI (finding ischemia via reflectance of light), a bioinspired, ingestible capsule designed for luminance-based diagnosis of AMI. Upon ingestion, the device activates in the small intestine’s pH environment, emitting pulses from three radially spaced white light-emitting diodes and measuring reflected light across 10 wavelengths. FIREFLI then computes a tissue luminance biomarker, which outperforms color-change biomarkers because of superior intrasubject consistency. The diagnosis is processed onboard and wirelessly transmitted to an external mobile device. In vivo studies in swine ( n = 9) demonstrated a diagnostic accuracy of 90%, with a sensitivity of 98% and specificity of 85%. By providing a noninvasive, real-time diagnostic solution, FIREFLI has the potential to facilitate earlier detection and treatment of AMI, ultimately improving patient outcomes.

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.

The oral route is the most patient-friendly option for drug administration, yet biological barriers often limit its effectiveness. Chief among these is the mucus layer along the gastrointestinal (GI) tract, which restricts the transport of drugs and carriers. Strategies such as mucolytics, mucus-inert materials, and anisotropic nanosystems have been employed to enhance penetration. We developed urease-powered poly(lactic-co-glycolic acid) (PLGA) nanomotors for drug delivery, featuring either random (isotropic) or spatially localized (anisotropic, Janus-like) urease surface functionalization. Anisotropic nanomotors were prepared by immobilizing PLGA nanoparticles (NPs) at the oil-water interface of Pickering emulsions, followed by urease conjugation via carbodiimide chemistry. Cryogenic scanning electron microscopy confirmed NPs interfacial localization, and immunoelectron microscopy unveiled urease spatial distribution. The resulting nanomotors catalyzed the conversion of urea to ammonia and carbon dioxide, enabling enhanced diffusion in urea-containing environments. Isotropic NPs showed a two-fold higher enzymatic conversion rate compared to anisotropic ones, attributed to higher enzyme availability, with negligible levels observed for passive PLGA NPs. All NPs were coated with poloxamer 407 (P407) for stabilization, yielding particles under 200 nm with low polydispersity and near-neutral charge. The P407 coating slightly reduced nanomotor mobility in fluids at the single-particle level, while it seems to have improved in vitro cell uptake in the presence of urea. In vivo studies in rats revealed that urease-functionalized nanomotors transited the GI tract and appeared to show enhanced localization at the epithelial surface, when compared to passive counterparts and regardless of urease distribution configuration. These findings highlight the potential of both isotropic and anisotropic urease-powered PLGA nanomotors to overcome GI barriers and serve as drug delivery platforms. STATEMENT OF SIGNIFICANCE: New designs for urease-powered polymeric nanoparticles (nanomotors) are proposed in this work to circumvent hurdles introduced by mucosae. Nanomotors featured either random or spatially oriented distribution of urease at their surface. The latter was achieved by means of Pickering emulsion and partial surface modification. Using these approaches, we demonstrated that both nanomotors convert urea into carbon dioxide and ammonia, resulting in enhanced diffusion in aqueous media. Nanomotors were safe in vitro, and capable of providing extensive distribution throughout the gastrointestinal tract following oral administration to rats, accumulating in the vicinity of the epithelium. The main findings suggest that such bioresorbable nanosystems have the potential to tackle important biological barriers and presumably be used as oral drug delivery vehicles.

Abstract Disclosure: M. Hudson: Syntis Bio. L. Sandoval: Syntis Bio. S. Pizzo: Syntis Bio. C. Dial: Syntis Bio. D. Sim: Syntis Bio. P.D. Susilo: Syntis Bio. F. Seta: 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 and related metabolic disorders by replicating the metabolic effects of gastric bypass through precise tissue coating. Developed in porcine models, it has demonstrated targeted nutrient blocking; however, its effects have yet to be demonstrated for weight loss, body composition, and hormonal regulation. We performed a comprehensive investigation characterizing these parameters in rodent models of obesity. Methods: Sprague-Dawley rats (20 weeks old, n=16) were maintained on an ad libitum high-fat diet (HFD, ResearchDiets D12492) for 12 weeks prior to study initiation to promote acclimation and induce weight gain. On Study Day 0, rats were pair-stratified by weight and randomly assigned to either the treatment group (SYNT-101, n=6) or control group (vehicle, n=6). The treatment group received a daily oral gavage of SYNT-101 (2 mL/kg), while the control group received saline (2 mL/kg). Throughout the 6-week study, body weight and food consumption were monitored daily, and body composition changes, including lean and fat mass, were assessed using EchoMRI, with a focus on epididymal and mesenteric white adipose tissue (eWAT and mWAT). Plasma samples were collected at both the study initiation (Day 0) and completion (Day 42) to assess metabolic and satiety hormone profiles. At the study’s conclusion, all rats were euthanized, and gastrointestinal tissue was harvested for further analysis. Results: SYNT-101 demonstrated visual evidence of transient deposition in the duodenum and showed a significant reduction in glucose uptake during OGTT. Clearance was visually confirmed within 24 hours of administration. The 6-week study demonstrated 1% body weight reduction each week and an average 10% daily reduction in food intake. Importantly, the treatment preserved lean muscle mass, while achieving a 20+% reduction in fat mass, including reductions in eWAT and mWAT. Additionally, DIO rats demonstrated outstanding tolerability throughout the 6-week treatment period. Conclusions: SYNT-101 demonstrates promising effects on weight loss, glucose metabolism, and body composition in DIO rodent models. Most notably, the treatment shows consistent, weekly weight loss, significantly reduced adiposity, while effectively preserving lean muscle mass, a critical limitation to existing weight loss interventions. These findings highlight the therapeutic potential of SYNT-101 for managing obesity and related metabolic disorders. Presentation: Sunday, July 13, 2025

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

This paper presents a Bluetooth Low Energy (BLE)-compatible transmitter (Tx) for the ingestible devices. To compensate for the varying communication losses caused by the surrounding environment, we propose the PA output power (<tex xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">$P_{\mathbf{P A}}$</tex>) calibration scheme, adaptively adjusting the supply voltage of the class-D power amplifier (DPA) through the dedicated LDO with the output power tuning range of 11.6 dB. This calibration is performed within the BLE preamble interval without sacrificing the additional latency. Moreover, the dual-mode operations of DPA configuring P-over-N PA and N-over-N PA maximize the PA efficiency of 49.7% and 54% at 1.6 dBm and <tex xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">$\mathbf{- 1 0 ~ d B m}$</tex>, respectively. Also, the proposed 2.4 GHz Tx supports GFSK modulation while meeting the BLE requirements without external crystal. Through wireless evaluation, the proposed BLE-compatible Tx maintains a constant input power of the receiver <tex xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">$(\mathbf{R x})\left(P_{\mathbf{R x}}\right)$</tex> under diverse conditions, thus alleviating the <tex xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">$\mathbf{R x}$</tex> sensitivity requirement and PVT variation of DPA.

The RNA medicine revolution has been spurred by lipid nanoparticles (LNPs). The effectiveness of an LNP is determined by its lipid components and their ratios; however, experimental optimization is laborious and does not explore the full design space. Computational approaches such as deep learning can be greatly beneficial, but the composite nature of LNPs limits the effectiveness of existing single molecule-based algorithms to LNPs. Addressing this, our approach integrates the multi-component and multimodal features of composite formulations such as LNPs to predict their performance in an end-to-end manner. Here we generate one of the largest LNP datasets (LANCE) by varying LNP formulations to train our deep learning model, COMET. This transformer-based neural network not only accurately predicts the efficacy of LNPs but is adaptable to non-canonical LNP formulations such as those with two ionizable lipids and polymeric materials. Furthermore, COMET can predict LNP performance in a cell line outside of LANCE and predict LNP stability during lyophilization using only small training datasets. Experimental validation showed that our approach can identify LNPs that exhibit strong protein expression in vitro and in vivo, promising accelerated development of nucleic acid therapies with extensive potential across therapeutic and manufacturing applications.

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

The multiple physiological effects of gut hormones in different metabolic tissues make them attractive therapeutic targets for the treatment of metabolic diseases. Currently, only glucagon-like peptide-1 (GLP-1) receptor-based agonists and oral dipeptidyl peptidase-4 inhibitors are available on the market. Despite their positive clinical outcomes across a range of indications, these treatments present several clinical challenges, including high costs, the need for peptide injections, and requirements for repeated administration. These limitations have driven research into improved GLP-1-based therapies, such as oral small-molecule agonists and novel drug delivery strategies based on emerging GLP-1 medicines. This article describes the challenges in clinical application and development of GLP-1-based pharmacotherapies. We review the development of oral small-molecule agonists and various drug delivery technologies, including ultralong-acting injectable technologies, continuous-acting implantable pumps, smart-acting electronic devices, nutrient-induced cell therapies, and noninvasive delivery systems. We discuss the current state of research, challenges to overcome, and opportunities to improve patient compliance and clinical outcomes. Additionally, we explore how endocrinological effects and patient-oriented needs can guide the development of advanced GLP-1 medicines.

Abstract Achieving long-term underwater adhesion to dynamic, regenerating soft substrates that undergo extreme fluctuations in pH and moisture remains a major unresolved challenge, with far-reaching implications for healthcare, manufacturing, robotics and marine applications 1–16 . Here, inspired by remoras—fish equipped with specialized adhesive discs—we developed the Mechanical Underwater Soft Adhesion System (MUSAS). Through detailed anatomical, behavioural, physical and biomimetic investigations of remora adhesion on soft substrates, we uncovered the key physical principles and evolutionary adaptations underlying their robust attachment. These insights guided the design of MUSAS, which shows extraordinary versatility, adhering securely to a wide range of soft substrates with varying roughness, stiffness and structural integrity. MUSAS achieves an adhesion-force-to-weight ratio of up to 1,391-fold and maintains performance under extreme pH and moisture conditions. We demonstrate its utility across highly translational models, including in vitro, ex vivo and in vivo settings, enabling applications such as ultraminiaturized aquatic kinetic temperature sensors, non-invasive gastroesophageal reflux monitoring, long-acting antiretroviral drug delivery and messenger RNA administration via the gastrointestinal tract.

Ingestible electronics offer a noninvasive way to monitor important physiological signals from the gastrointestinal (GI) tract, which may open a new era in healthcare. However, it faces challenges with energy constraints and data privacy. Attacks on unprotected wireless communication can result in dangerous outcomes. In addition, conventional cryptography schemes are proven vulnerable to quantum computer attacks. Previous works either do not ensure post-quantum security or overlook the need for low energy consumption. Thus, we propose an ultra low-power hardware solution which is post-quantum secure protocol for an ingestible device. First, by combining Lightweight Cryptography (LWC) and mutually authenticated key exchange (MAKE) in Post-Quantum Cryptography (PQC), we reduce the energy consumption of enc/decryption by 59.12/61.42% by using LWC and that of key exchange with mutual authentication 75.82% by not including expensive post-quantum secure digital signature algorithm. In addition to the proposed protocol, we take a duty-cycling approach with a timer to wake the device from deep sleep mode (consuming less than 0.00025 mA). Based on our analysis for a practical scenario, we show that the overhead of cryptographic operations is compensated by using duty-cycling resulting in the lowest energy mode in hardware. Even when calling the most expensive cryptographic operation, PQC-based key exchange, for each data communication session, we can save energy by at least 67.66×.

Punch biopsy is a skin biopsy method that is used to remove a small sample of the epidermis and dermis. The procedure requires a trained dermatologist to excise the sample with a punch biopsy tool and then immediately apply sutures for wound closure. Punch biopsy is a common procedure necessary for the diagnosis of many conditions. Thus, the present shortage of dermatologists-especially in the developing world-motivates the design of convenient methods for punch biopsy that do not require clinical training. Here, we present a medical device that streamlines punch biopsy and wound closure into simple, sequential operations. The handheld device engages and securely locks the skin, excises the biopsy sample, then applies a N-butyl cyanoacrylate tissue adhesive for wound closure. The device is validated ex vivo using porcine ear skin, which has comparable biomechanical properties to human skin. For engagement, the device can target the desired biopsy area with an accuracy of 2 mm. For sample collection, the device reliably excises samples 7 mm in diameter and 4 mm in depth. For wound closure, the device streamlines the application of tissue adhesive to seal the wound, albeit with less strength than surgical sutures. Altogether, these results validate the design of a device for punch biopsy and wound closure that can be used within sequential steps with minimal training.

Background and Aims: Inadequate insufflation is a common problem during colonoscopies, with gas leakage from the anus hindering luminal visualization. This study examines the prevalence of this problem through a survey of gastroenterologists, which motivated the development of our insufflation leakage management rectal seal device, RECSEAL. Methods: The RECSEAL was developed based on the need identified from gastroenterologists regarding the rate and management methods of inadequate insufflation. The RECSEAL, measuring 55 mm in diameter and 50 mm in length, was designed and silicone injection-molded to safely insert and reside in the anal canal without migrating or hindering movement of the colonoscope. To evaluate the RECSEAL, a colonoscope was outfitted with a pressure sensor to measure colonic pressure while visualizing the lumen in a bench, ex vivo, and in vivo in pig models. In the ex vivo study, a small injury was introduced to the anal sphincter to simulate poor anal tone. Results: < .0001) mean pressures with the RECSEAL (32-33 mm Hg) than the control (0.3-3.6 mm Hg). The seal improved lumen visualization in the collapsed colon with inadequate insufflation. The RECSEAL was shown to be feasible in an in vivo model. Conclusions: The flexible RECSEAL allowed higher luminal pressures in the colon and may improve colon insufflation and visualization.

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.

While most oncologists know that many chemotherapies are dosed on a body surface area (BSA) basis, fewer know that the equations used to estimate BSA are based on a study done over 100 years ago using data from just 9 people. Moreover, two patients with the same BSA can have many factors, such as body composition and genetics, which can impact a drug’s pharmacokinetics and pharmacodynamics, resulting in worse therapeutic outcomes. To solve this problem, we developed a medical device that can personalize the dose of chemotherapy to the patient during an infusion center visit. Our medical device, which we call CLAUDIA (the Closed-Loop AUtomated Drug Infusion regulator) is a closed-loop drug delivery system that measures the concentration of drug and changes the infusion rate in real time to keep the concentration of drug within the therapeutic window. CLAUDIA uses high performance liquid chromatography-mass spectrometry (HPLC-MS) as the sensor, which allows it to be relatively easily translated to control many different drugs, either individually or in a combination chemotherapy regimen. We demonstrate CLAUDIA can control the concentration of 5-fluorouracil (5-FU) in rabbits, which were manipulated to capture the pharmacokinetic variability observed clinically. We then adapted CLAUDIA to also control the concentration of irinotecan, demonstrating its ability to be rapidly translated to additional chemotherapies. Finally, we perform a cost-effectiveness analysis that demonstrates that CLAUDIA is cost-effective compared to the current standard of care for drug dosing of 5-FU (i.e., BSA). Overall, CLAUDIA presents promising medical device that can personalize the dosing of chemotherapy, which may be able to improve the therapeutic outcomes for multiple chemotherapies. Citation Format: Louis DeRidder, Kyle Hare, Ted Smierciak, Mia Chao, Aaron Lopes, Josh Jenkins, Nina Fitzgerald, Emmeline MacPherson, Niora Fabian, Josh Morimoto, Jacqueline Chu, Ameya Kirtane, Wiam Madani, Keiko Ishida, Johannes Kuosmanen, Naomi Zecharias, Christopher Colangelo, Hen-Wei Huang, Makaya Chilekwa, Nikhil Lal, Shriya Srinivasan, Alison Hayward, Brian Wolpin, David Trumper, Troy Quast, Douglas Rubinson, Robert Langer, Giovanni Traverso. Closed-loop drug delivery system to personalize chemotherapy dosing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1847.

Advances in personalized medicine are spurring the development of ingestible electronics for controlled, on-demand drug delivery in the gastrointestinal (GI) tract, enhancing therapeutic efficacy further beyond traditional oral pills. These systems rely on electronically controlled drug release actuation mechanisms, like micropumps [1] and reservoir-based designs [2], for precision dosing [3], [4]. However, they often require substantial energy and space [5]. While conventional batteries have powered ingestible electronics, they pose challenges due to their bulkiness, limited energy density, and safety risks associated with toxic materials [6], [7]. Consequently, battery-free energy harvesting solutions and energy-efficient drug delivery actuation mechanisms are crucial for progress in this field. Among other energy-harvesting methods, such as thermal or vibrational energy harvesters, a galvanic cell (GC), which converts chemical energy from acidic GI fluid, is particularly well-suited for high-power applications like drug delivery [6]. However, the maximum power point (MPP) of GC is a nonlinear function of pH and opencircuit voltage [2], necessitating the sampling of real-time pH data of the GI fluid to perform maximum power point tracking (MPPT) for efficient energy harvesting. For drug delivery, a reservoir-based system sealed with an electrochemically dissolvable metal membrane offers a compact design and protection of sensitive payloads such as unstable drugs from the harsh environment of the GI tract [2], [8]. However, the activation voltage for dissolving the metal membrane of the reservoirbased systems also varies with pH, further highlighting the need to sample the GI pH in real-time [9].

High Resolution Image Download MS PowerPoint Slide Oral drug delivery is a widely preferred method of drug administration due to its ease of use and convenience for patients. Localization of drug release in the gastrointestinal (GI) tract is important to treat localized diseases and maximize drug absorption. However, achieving drug localization in the dynamic GI tract is challenging. To address this challenge, we leveraged the geographic diversity of the GI tract by targeting its mucus layers, which coat the epithelial surfaces. These layers, composed of mucin glycoproteins, are synthesized with unique chemical compositions and expressed in different regions, making them ideal targets for drug localization. In this article, we identify cyclic peptides that bind selectively to MUC2 (in the intestines) and MUC5AC (in the stomach), serving as targeting ligands to these regions of the GI tract. We demonstrate the effectiveness of these peptides through in vitro, ex vivo, and in vivo experiments, showing that incorporating these targeting ligands can increase binding and selectivity 2-fold to the desired regions, thus potentially overcoming challenges with localizing drug distribution in oral delivery. These results indicate that cyclic peptides can be used to localize drug cargoes at certain sites in the body compared to free drugs.

Implantable systems for neurological chronotherapy are poised to revolutionize the treatment of central nervous system diseases and disorders. These devices enable precise, time-controlled drug delivery aligned with the body's circadian rhythms, optimizing therapeutic outcomes. By bypassing the blood-brain barrier, they achieve high local drug concentrations while minimizing systemic side effects, offering significant advantages for conditions where traditional therapies often fall short. Platforms like SynchroMed II and CraniUS showcase this innovation, providing programmable delivery for conditions such as epilepsy and glioblastoma, with customizable profiles ranging from continuous infusion to timed bolus administration. Preclinical and clinical studies underscore the efficacy of aligning drug delivery with circadian rhythms, enhancing outcomes in chrono-chemotherapy and anti-epileptic treatments. Despite their promise, challenges remain, including the invasiveness of implantation within the brain, device longevity, synchronization complexities, and cost(s). Accordingly, this review explores the current state of implantable neurological systems that may be leveraged for chronotherapy, their applications, limitations, and potential to transform neurological disease/disorder management.

Oral drug delivery is a widely used method of drug administration; however, achieving localized drug release at specific regions of the gastrointestinal (GI) tract is generally accomplished by using broad environmental differences. The GI tract is a complex system with regional differences in composition, such as selective expression of mucin glycoproteins in different organs. Here, we identify small molecule ligands that can selectively bind to the different mucins to localize drug delivery to the small intestine and stomach. We demonstrate up to a 10-fold increase in particle binding to these organs and up to a 4-fold increase in selectivity compared to chitosan. Additionally, we observe up to a 9-fold increase in budesonide concentration in the small intestine and a 25-fold increase in tetracycline concentration in the stomach. These results show that we have developed a versatile platform capable of sequestering a variety of drugs in certain GI tract organs.

Abstract Injectable drug depots have transformed our capacity to enhance medication adherence through dose simplification. Central to patient adoption of injectables is the acceptability of needle injections, with needle gauge as a key factor informing patient discomfort. Maximizing drug loading in injectables supports longer drug release while reducing injection volume and discomfort. Here, to address these requirements, we developed self-aggregating long-acting injectable microcrystals (SLIM), an injectable formulation containing drug microcrystals that self-aggregate in the subcutaneous space to form a monolithic implant with a low ratio of polymer excipient to drug (0.0625:1 w/w). By minimizing polymer content, SLIM supports injection through low-profile needles (&lt;25 G) with high drug loading (293 mg ml −1 ). We demonstrate in vitro and in vivo that self-aggregation is driven by solvent exchange at the injection site and that slower-exchanging solvents result in increased microcrystal compaction and reduced implant porosity. We further show that self-aggregation enhances long-term drug release in rodents. We anticipate that SLIM could enable low-cost interventions for contraceptives.

mRNA vaccines consist of antigen-encoding mRNA, which produces the antigenic protein upon translation. Coupling antigen production with innate immune activation can generate a potent, antigen-specific T-cell response. Clinical reports have demonstrated the ability of mRNA vaccines to elicit an anticancer immune response against various tumor types. Here, we discuss strategies to enhance the potency of mRNA vaccines. We provide an overview of existing knowledge regarding the activation and trafficking mechanisms of mRNA vaccines and share optimization strategies to boost mRNA-mediated antigen production. In addition, we address methods to target mRNA vaccines to dendritic cells and lymph nodes, key initiators of the immune response. Finally, we review strategies for enhancing immune activation using adjuvants compatible with mRNA vaccines. mRNA vaccines offer unique advantages that can be utilized for oncology applications. However, significant work is needed to understand their underlying mechanisms and develop technologies to improve their effectiveness.

Injectable drug depots have transformed our capacity to enhance medication adherence through dose simplification. Central to patient adoption of injectables is the acceptability of needle injections, with needle gauge as a key factor informing patient discomfort. Maximizing drug loading in injectables supports longer drug release while reducing injection volume and discomfort. Here, to address these requirements, we developed self-aggregating long-acting injectable microcrystals (SLIM), an injectable formulation containing drug microcrystals that self-aggregate in the subcutaneous space to form a monolithic implant with a low ratio of polymer excipient to drug (0.0625:1 w/w). By minimizing polymer content, SLIM supports injection through low-profile needles (&lt;25 G) with high drug loading (293 mg ml−1). We demonstrate in vitro and in vivo that self-aggregation is driven by solvent exchange at the injection site and that slower-exchanging solvents result in increased microcrystal compaction and reduced implant porosity. We further show that self-aggregation enhances long-term drug release in rodents. We anticipate that SLIM could enable low-cost interventions for contraceptives.

Establishing a robust and intimate mucosal interface that allows medical devices to remain within lumen-confined organs for extended periods has valuable applications, particularly for gastrointestinal theranostics. Here, we report the development of an electroadhesive hydrogel interface for robust and prolonged mucosal retention after electrical activation (e-GLUE). The e-GLUE device is composed of cationic polymers interpenetrated within a tough hydrogel matrix. An e-GLUE electrode design eliminated the need for invasive submucosal placement of ground electrodes for electrical stimulation during endoscopic delivery. With an electrical stimulation treatment of about 1 minute, the cationic polymers diffuse and interact with polyanionic proteins that have a relatively slow cellular turnover rate in the deep mucosal tissue. This mucosal adhesion mechanism increased the adhesion energy of hydrogels on the mucosa by up to 30-fold and enabled in vivo gastric retention of e-GLUE devices in a pig stomach for up to 30 days. The adhesion strength was modulated by polycationic chain length, electrical stimulation time, gel thickness, cross-linking density, voltage amplitude, polycation concentration, and perimeter-to-area ratio of the electrode assembly. In porcine studies, e-GLUE demonstrated rapid mucosal adhesion in the presence of luminal fluid and mucus exposure. In proof-of-concept studies, we demonstrated e-GLUE applications for mucosal hemostasis, sustained local delivery of therapeutics, and intimate biosensing in the gastrointestinal tract, which is an ongoing clinical challenge for commercially available alternatives, such as endoclips and mucoadhesive. The e-GLUE platform could enable theranostic applications across a range of digestive diseases, including recurrent gastrointestinal bleeding and inflammatory bowel disease.

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. Radiation-therapy-induced DNA damage in oral and rectal epithelial cells can be reduced via the nanoparticle-mediated local delivery of messenger RNA encoding for a damage-suppressor protein found in radiation-resistant tardigrades.

Wearable sensors are transforming our capacity to monitor a broad range of activities for recreation and health purposes. Developing low-cost personalized sensors on a range of materials could enable broad applicability irrespective of the material substrate. Here, the methods of fabrication, characterization, and application of kirigami graphene strain sensors are described. The dynamic range of these sensors is characterized, showing that the kirigami structure enhances application-specific device performance, demonstrating that this strategy is applicable to a range of materials. We apply this strategy to develop personalized sensors for a variety of measurement frequencies and biological phenomena including evaluation of abdominal distention and respiration in a pig model, as well as human heart rate measurement, limb actuation, and hand gesture interpretation in human volunteers. Through these experiments, we show that this low-cost strategy for customized graphene sensors can be broadly applied across a range of consumer and health applications.

Tissue repair is often impaired in pathological states, highlighting the need for innovative wound-healing technologies. This study introduces composite hyaluronic acid gas-entrapping materials (GEMs) delivering carbon monoxide (CO) to promote wound healing in pigs. These composite materials facilitate burst release followed by sustained release of CO over 48 h. In a porcine full-thickness wound model, CO-GEMs significantly accelerated wound closure compared to the standard-of-care dressing (Tegaderm). Wound area closure with CO-GEMs was 68.6% vs 56.8% on day 14, 41.0% vs 25.1% on day 28, and 26.9% vs 11.8% on day 42, effectively reducing healing time by 14 days. Histological analysis revealed increased epithelialization and neovascularization with reduced inflammation. These findings demonstrate the potential of CO-GEMs as a topical therapeutic to enhance tissue repair in clinically relevant models, supporting further testing for wound-healing applications.

Intragastric balloon therapy, a treatment for obesity, has several limitations, including a lack of persistent weight loss. Static intragastric balloons, which maintain a constant volume, appear to be associated with accommodation and plateauing of weight loss in large mammals. In this study, we present the oscillating satiety induction and regulation intragastric system (OSIRIS), an endoscopically administered gastric resident device that supports dynamic satiety induction, approximating the natural satiety induction process associated with episodic meal ingestion. The OSIRIS expands pre-prandially, occupying the gastric cavity, and then shrinks to a minimal volume after the meal. We have developed two gastric residency and dynamic expansion mechanisms based on motorized and balloon approaches. The OSIRIS is programmed to stimulate satiety autonomously throughout the treatment without manual assistance. We have conducted preliminary in vivo evaluations in a swine model, demonstrating decreased food intake. The OSIRIS enables minimally invasive dynamic satiety induction with the potential to support weight loss.