Controlling the molecular transport of nutrients through the gut is an attractive strategy to modulate host metabolism. Herein, a technique of stress-based evolution of an individual's own microbiota to enhance lipid metabolism is presented, which is based on sequential culture of these bacteria in higher concentrations of lipids. Using this technique, a probiotic formulation of bacterial colonies that exhibit increased lipid metabolism was generated from oral microbiota samples from mice, canine, and human sources. Mice fed a high-fat diet (HFD) and administered lipid stress evolved (LSE) probiotics excreted increased lipids in stool and reduced triglyceride transport into the blood by three-fold till 3 h post-oral gavage of soybean oil, as compared to controls. In addition, these enhanced probiotics prevented weight gain in mice fed a HFD five-fold better than controls and induced weight loss in mice with diet change three-fold faster than diet change alone. In these mice, there was a marked change in appearance with a more healthy, less oily coat. Controlled metabolic cage experiments demonstrated that the total movement, food intake, and water intake were not significantly different between mice receiving LSE probiotic versus a control probiotic formulation, suggesting that important health measures are unchanged with LSE probiotic administration. Overall, this facile stress-based culture technique can be utilized to modulate bacterial metabolism and applied to different industrial processes of probiotic generation and to affect different disease outcomes such as obesity.

Abstract Tumor‐associated macrophages (TAMs) shape the tumor microenvironment through plastic transitions between pro‐inflammatory M1‐like and immunosuppressive M2‐like states, yet clinical drug therapies are limited by toxicity, resistance, and delivery barriers. This review explains how non‐invasive physical stimulation (NIPS) reprograms TAMs via defined couplings between physical inputs and signaling pathways. Hypoxia‐tolerant photodynamic strategies and mild photothermal heating reset hypoxia‐ and lactate‐driven programs; cavitation‐dominant ultrasound and sonodynamic therapy trigger danger signaling and reactive oxygen species; ultrasound microbubble destruction provides endothelial repair cues; nanosecond pulsed electric fields activate cyclic GMP‐AMP synthase–stimulator of interferon genes (cGAS–STING) pathway; piezoelectric materials convert mechanical input into calcium‐dependent transcription; and appropriately dosed radiotherapy elicits immune‐active responses while avoiding hypoxia‐driven M2 recruitment. Across models, these regimens promote pro‐inflammatory reprogramming, normalize aberrant vasculature, and strengthen antitumor immunity while restraining immunosuppression. We synthesize parameter windows, delivery options, and combination strategies with checkpoint blockade and macrophage‐directed agents to guide the translation of NIPS into precise, low‐toxicity TAM‐targeted immunotherapy.

Effective dry-state stabilization of bacteriophages is crucial for expanding their therapeutic use. This study builds on previous findings that saccharide-based formulations maintain phage stability when the glass transition temperature (Tg) exceeds the storage temperature (Ts) by approximately 50°C. We investigated polymer-based matrices for long-term stabilization by spray-drying PEV1 phage with polyvinylpyrrolidone (PVP) of varying molecular weights (K15, K25, K40, K100) and storing for 180 days at temperatures (4, 22, and 40°C) and relative humidity (15%, 33%, 43%, and 53% RH). All formulations achieved minimal titre losses (≤1 log10) at 4 and 22°C under 15% RH. Differential scanning calorimetry (DSC) demonstrated Tg increased with PVP molecular weight but decreased substantially with humidity (30-50°C reduction per 20% RH increase). At 33% RH, long-term stability was achieved with high-molecular-weight PVPs (K40, K100), which maintained thermal offsets between Tg and Ts (ΔT ≥ 100°C), while lower-weight (K15, K25) showed 2-3 log10 titre loss. Water activity (aw) analysis revealed a critical threshold at aw 0.43, above which degradation kinetics increased by approximately a tenfold rate. Arrhenius analysis confirmed that phage degradation rates increased with temperature, consistent with thermally activated destabilization mechanisms. Under higher stress conditions (40°C/≥43% RH), water absorption plasticized the PVP matrix and depressed the Tg while elevated temperature simultaneously accelerated degradation kinetics, resulting in substantial titre losses even when ΔT exceeded 100°C. In conclusion, at mild humidity (aw ≤ 0.33) and ambient temperature (≤22°C), high-molecular-weight PVP-based formulations can offer enhanced storage flexibility and reduced cold-chain dependency for optimal therapeutic viability.

Gene therapy has advanced considerably in recent years, driven by innovations in vector engineering and a more advanced understanding of virology for clinical translation. Since 2021, the U.S. Food and Drug Administration (FDA) has approved seven new viral vector‐based gene therapies, five of which use adeno‐associated virus (AAV) vectors, reinforcing their status as the leading platform for in vivo gene delivery. These approvals encompassed hematologic, neuromuscular, dermatologic, and neurogenetic diseases, using diverse serotypes and delivery routes tailored to the therapeutic context. Disease‐specific patterns of capsid usage reveal advancement in tailored capsid engineering based on anatomical targeting needs. Beyond AAV, non‐AAV vectors, such as herpes simplex virus (HSV) and adenovirus, are actively explored in cancer trials, while lentiviral vectors support applications in oncology and immune‐related disorders. This review provides an updated analysis of the clinical landscape of viral vector‐based gene therapies, highlighting new FDA‐approved products and ongoing clinical trials by vector type, disease indication, and clinical phase since our original review in 2021. Our analysis highlights advances in viral vector technologies that reflect a maturing field, transitioning from proof‐of‐concept studies to precision platforms increasingly capable of addressing rare monogenic disorders and more prevalent, complex diseases.

Mesenchymal stromal cell (MSCs)-based therapies have emerged as a promising approach for inflammatory bowel disease (IBD) treatment due to their immunosuppressive and regenerative properties. However, clinical trials have shown limited therapeutic effectiveness, largely because of low efficiency in penetrating the inflamed colon and their inconsistent in vivo immunomodulatory ability. In this study, we generated genetically engineered adipose-derived human MSCs constitutively expressing CXC chemokine receptor 4 and interleukin 10 (CXCR4-IL10-MSCs) to promote their delivery to the inflamed colon and enhance their immunosuppressive capability. Compared to unmodified MSCs, CXCR4-IL10-MSCs exhibited enhanced trafficking to the inflamed colon and achieved improved therapeutic effects in dextran sulfate sodium (DSS)-challenged colitic mice. Upon a chronic DSS re-challenge, CXCR4-IL10-MSCs showed enhanced long-term protective effects. These findings demonstrate that stable ectopic expression of CXCR4 and IL10 enhances the therapeutic efficacy of MSCs and supports the development of an optimized MSC-based product capable of inducing an improved long-term protective immune memory in IBD.

Acute kidney injury (AKI) is a serious condition with significant global impact. To explore mechanisms and biomarkers of heat‐stress‐induced AKI, we used human kidney organoids derived from induced pluripotent stem cells via suspension culture. Organoids were exposed to 37, 39, and 41°C. At 41°C, we found the viability decreased over time, with cytoskeleton damage, impaired tubule absorption, apoptosis, and collagen deposition. Under extreme heat (41°C), elevated AKI markers KIM‐1 and NGAL, along with cell cycle arrest markers TIMP‐2*IGFBP7 were detected. Notably, TIMP‐2*IGFBP7 appeared at 12 h post‐exposure, preceding NGAL and KIM‐1. Nascent and steady‐state RNA analyses revealed suppressed oxidative phosphorylation and ATP metabolism, along with elevated histone expression, implicating their roles in heat‐induced AKI. The data support that kidney organoids serve as a valuable model for investigating heat‐induced AKI, providing insights into early injury biomarkers that are valuable for the development of treatments.

Ureteral carcinoma remains a major clinical challenge and requires effective localized treatment. Here, we report a novel 125I seed brachytherapy (ISB) and doxorubicin (DOX) chemotherapy integrated ureteral stent (IUS), which enables simultaneous urinary drainage and chemoradiotherapy. This study was divided into three parts. First, ISB and DOX significantly reduced T24 cell viability and inhibited migration and invasion in an in vivo study (p < 0.01). Second, a T24 xenograft mouse model demonstrated that the (DOX + ISB) group exhibited greater tumor suppression than the DOX (p = 0.08) and ISB (p = 0.02) groups, with decreased Ki‐67 and Bcl‐2 expression and increased apoptosis (all p < 0.01) in an in vitro study. Third, the IUS was successfully implanted in normal beagle dogs (n = 30) without surgical complications. The ureteral diameter increased with increasing cumulative brachytherapy and sustained DOX release (p < 0.05). Histological analysis revealed progressive tissue damage and fibrosis, with increased expression of α‐SMA, Caspase‐3, and Collagen‐1 in the 0.8 mCi + 20 mg DOX group (p < 0.05), whereas PCNA expression was highest in the Control group (0 mCi + 0 mg DOX). In conclusion, the newly designed IUS is safe and technically feasible in animals; clinical studies will be required to evaluate its use in humans.

Human skin‐derived neural crest (NC)‐like stem cells present a highly accessible, autologous source of multipotent cells, with the potential to differentiate into a variety of cell types, including Schwann cells (SCs). However, these cells quickly lose their stem‐like characteristics in vitro and eventually limit their ability to form functional SCs. To overcome this, we investigated SOX10 upregulation, the key regulator of NC formation and multipotency, using both small chemical (Forskolin and RepSox) treatment and genetic modification. Remarkably, SOX10 upregulation highly increased SC gene expression instead of NC markers, though Forskolin‐RepSox also triggered melanocytic and smooth muscle gene markers alongside reduced NC genes. In contrast, genetic SOX10 upregulation enhanced both SOX10 and NC gene expression without inducing alternative lineages. Continuous SOX10 expression was necessary for increased SC protein markers, and differentiating SOX10‐overexpressing cells on immobilized NRG1 further enhanced SC markers and induced a distinct, elongated morphology typical for myelinating SCs. Therefore, this study introduces a rapid, efficient method to derive SC‐like cells from the skin‐derived NCs, highlighting their potential in regenerative medicine for cell therapy and disease modeling applications.

An abdominal aortic aneurysm (AAA) is a life‐threatening vascular condition characterized by the dilation of the abdominal aorta, with ferroptosis playing a significant role in its pathogenesis. This study investigates the therapeutic potential of engineering biomimetic nanovesicles to deliver phosphatidylethanolamine‐binding protein 1 (PEBP1) mRNA for inhibiting ferroptosis in vascular smooth muscle cells (VSMCs) and preventing AAA progression. Differential gene expression analysis of the AAA transcriptomic dataset GSE57691 identified 243 differentially expressed genes (DEGs), intersecting with 12 ferroptosis‐related genes. Single‐cell analysis of dataset GSE237230 highlighted PEBP1 as a key gene in VSMCs. Overexpression of PEBP1 in VSMCs enhanced proliferation, reduced reactive oxygen species (ROS) and iron levels, and inhibited apoptosis and ferroptosis via the NRF2/GPX4 axis. The engineered biomimetic nanovesicles demonstrated significant uptake by VSMCs and effective delivery of PEBP1 mRNA. In vivo studies confirmed that these nanovesicles substantially inhibited AAA progression in mice. This study presents a novel bioengineering approach for AAA treatment by targeting ferroptosis through PEBP1 mRNA delivery, offering a promising molecular strategy for the prevention and management of AAA.

Chemical ablative therapies offer effective alternatives for tumor treatment, particularly when surgical resection or heat‐based ablation therapies are unsuitable due to the tumor's stage, location, or extent. Photodynamic therapy (PDT), which involves delivering light‐activated, tumor‐killing photosensitizers, and percutaneous ethanol injection (PEI), which involves the direct injection of pure ethanol into tumor nodules, are two non‐heat‐based chemical ablative methods that have been proven safe with low adverse effects for unresectable tumors. We have investigated combining these two treatments using a new formulation known as BPD‐EC‐EtOH. This formulation includes three components: (1) benzoporphyrin derivative, a commonly used photosensitizer for PDT; (2) ethyl cellulose (EC), an FDA‐approved polymer that forms a gel in the water phase and enhances drug retention; and (3) pure ethanol for PEI application. Here, we demonstrated the localization of BPD and confirmed that it retains its photochemical properties within the EC‐EtOH gel in tissue‐mimicking phantoms and in swine liver tissues. We also characterized EC's ability to act as a light‐scattering agent, which effectively extends light propagation distance in both in vitro models and ex vivo porcine liver tissues, potentially overcoming the limitations of light penetration in pigmented organs. We then investigated the therapeutic effects of BPD‐EC‐EtOH using two well‐established subcutaneous animal models of hepatocellular carcinoma and pancreatic ductal adenocarcinoma, both in single‐ and multi‐cycle combination treatments, showing tumor‐killing effects. These findings highlight the potential of BPD‐EC‐EtOH as a novel therapeutic approach, effective with either single or multi‐cycle treatment sessions.