Recent advances in delivery systems for transcription factors (TFs) have opened new therapeutic opportunities in regenerative medicine, cancer therapy, and genetic disorders. However, effective TF delivery still faces substantial obstacles, including limited cellular uptake, inefficient nuclear translocation, low cargo stability, and insufficient target specificity. Furthermore, artificial TFs have enabled targeted modulation of gene expression, further expanding their therapeutic potential. This review comprehensively discusses current progress in TF delivery methodologies, including direct TF protein delivery using cell-penetrating peptides, and extracellular vesicles, as well as TF gene delivery approaches utilizing both lipid-based nanoparticles and viral strategies. Notably, engineered nanoparticles have emerged as promising platforms due to their precise control over TF delivery, improved specificity, and minimized off-target effects. Despite these significant advancements, major hurdles in delivery efficiency, cargo stability, and overall safety persist. Overcoming these obstacles will be essential to accelerate the clinical translation of TF-based therapeutics for a broad spectrum of diseases.

Chronic colonic inflammation is a feature of cancer and is strongly associated with tumorigenesis, but its underlying molecular mechanisms remain poorly understood. Inflammatory conditions increased ITF2 and p65 expression both ex vivo and in vivo, and ITF2 and p65 showed positive correlations. p65 overexpression stabilized ITF2 protein levels by interfering with the binding of Parkin to ITF2. More specifically, the C-terminus of p65 binds to the N-terminus of ITF2 and inhibits ubiquitination, thereby promoting ITF2 stabilization. Parkin acts as a E3 ubiquitin ligase for ITF2 ubiquitination. Intestinal epithelial-specific deletion of ITF2 facilitated nuclear translocation of p65 and thus increased colitis-associated cancer tumorigenesis, which was mediated by Azoxymethane/Dextran sulfate sodium or dextran sulfate sodium. Upregulated ITF2 expression was lost in carcinoma tissues of colitis-associated cancer patients, whereas p65 expression much more increased in both dysplastic and carcinoma regions. Therefore, these findings indicate a critical role for ITF2 in the repression of colitis-associated cancer progression and ITF2 would be an attractive target against inflammatory diseases including colitis-associated cancer.

Recent advances in delivery systems for transcription factors (TFs) have opened new therapeutic opportunities in regenerative medicine, cancer therapy, and genetic disorders. However, effective TF delivery still faces substantial obstacles, including limited cellular uptake, inefficient nuclear translocation, low cargo stability, and insufficient target specificity. Furthermore, artificial TFs have enabled targeted modulation of gene expression, further expanding their therapeutic potential. This review comprehensively discusses current progress in TF delivery methodologies, including direct TF protein delivery using cell-penetrating peptides, and extracellular vesicles, as well as TF gene delivery approaches utilizing both lipid-based nanoparticles and viral strategies. Notably, engineered nanoparticles have emerged as promising platforms due to their precise control over TF delivery, improved specificity, and minimized off-target effects. Despite these significant advancements, major hurdles in delivery efficiency, cargo stability, and overall safety persist. Overcoming these obstacles will be essential to accelerate the clinical translation of TF-based therapeutics for a broad spectrum of diseases.

Chronic colonic inflammation is a feature of cancer and is strongly associated with tumorigenesis, but its underlying molecular mechanisms remain poorly understood. Inflammatory conditions increased ITF2 and p65 expression both ex vivo and in vivo, and ITF2 and p65 showed positive correlations. p65 overexpression stabilized ITF2 protein levels by interfering with the binding of Parkin to ITF2. More specifically, the C-terminus of p65 binds to the N-terminus of ITF2 and inhibits ubiquitination, thereby promoting ITF2 stabilization. Parkin acts as a E3 ubiquitin ligase for ITF2 ubiquitination. Intestinal epithelial-specific deletion of ITF2 facilitated nuclear translocation of p65 and thus increased colitis-associated cancer tumorigenesis, which was mediated by Azoxymethane/Dextran sulfate sodium or dextran sulfate sodium. Upregulated ITF2 expression was lost in carcinoma tissues of colitis-associated cancer patients, whereas p65 expression much more increased in both dysplastic and carcinoma regions. Therefore, these findings indicate a critical role for ITF2 in the repression of colitis-associated cancer progression and ITF2 would be an attractive target against inflammatory diseases including colitis-associated cancer.

Surgery is unanimously regarded as the primary strategy to cure solid tumors in the early stages but is not always used in advanced cases. However, tumor surgery must be carefully considered because the risk of metastasis could be increased by the surgical procedure. Tumor surgery may result in a deep wound, which induces many biological responses favoring tumor metastasis. In particular, NETosis, which is the process of forming neutrophil extracellular traps (NETs), has received attention as a risk factor for surgery-induced metastasis. To reduce cancer mortality, researchers have made efforts to prevent secondary metastasis after resection of the primary tumor. From this point of view, a better understanding of surgery-induced metastasis might provide new strategies for more effective and safer surgical approaches. In this paper, recent insights into the surgical effects on metastasis will be reviewed. Moreover, in-depth opinions about the effects of NETs on metastasis will be discussed.

Chronic wounds are often characterized by prolonged inflammation, impaired angiogenesis, and dysregulated hypoxic response, partly caused by the insufficient activation of hypoxia-inducible factor-1 alpha (HIF-1α). This study investigated the potential of engineered extracellular vesicles (EVs) to deliver a stable, constitutively active form of HIF-1α (scHIF-1α) to promote wound healing. A collagen-binding domain (CBD) was integrated into EVs to enhance their retention at wound sites, and collagen sponges were employed as scaffolds to ensure sustained, localized release of scHIF-1α EVs. In vitro studies have demonstrated that scHIF-1α EVs significantly improved cell proliferation, migration, and angiogenesis in dermal fibroblasts, endothelial cells, and keratinocytes-key cells involved in the wound healing process. In vivo, scHIF-1α EVs accelerated wound closure, enhanced tissue regeneration, and promoted angiogenesis in various wound healing models, including excisional wounds, surgical skin flaps, and diabetic wounds. The integration of CBD further enhanced EV retention, amplifying therapeutic outcomes. These results propose that scHIF-1α delivery via EVs, particularly when combined with collagen-based sustained-release systems, offers a promising and patient-friendly therapeutic strategy for treating chronic wounds.

<b>Background/Objectives:</b> Diabetes mellitus (DM) is an increasingly prevalent endocrine disorder affecting humans and companion animals. Type 1 DM (T1DM) and type 2 DM (T2DM) are well characterized in humans, and canine DM most often resembles T1DM, marked by insulin dependence and β-cell destruction. Conversely, feline DM shares key features with human T2DM, including insulin resistance, obesity-related inflammation, and islet amyloidosis. This review provides a comprehensive comparative analysis of antidiabetic therapies in humans, dogs, and cats, focusing on three core areas: disease pathophysiology, pharmacological and delivery strategies, and translational implications. In human medicine, a wide array of insulin analogs, oral hypoglycemic agents, and incretin-based therapies, including glucagon-like peptide-1 receptor agonists (liraglutide) and sodium-glucose cotransporter-2 inhibitors (empagliflozin), are available. Veterinary treatments remain limited to species-adapted insulin formulations and off-label use of human drugs. Interspecies differences in gastrointestinal physiology, drug metabolism, and behavioral compliance influence therapeutic efficacy and pharmacokinetics. Recent innovations, such as microneedle patches for insulin delivery and continuous glucose monitoring systems, show promise in humans and animals. Companion animals with naturally occurring diabetes serve as valuable models for preclinical testing of novel delivery platforms and long-acting formulations under real-world settings. While these technologies show potential, challenges remain in regulatory approval and behavioral adaptation in animals. <b>Conclusions:</b> Future research should prioritize pharmacokinetic bridging studies, veterinary-specific formulation trials, and device validation in animal models. By highlighting shared and species-specific characteristics of DM pathogenesis and treatment, this review advocates a One Health approach toward optimized antidiabetic therapies that benefit human and veterinary medicine.

Ovarian cancer remains one of the most lethal gynecologic malignancies, primarily due to late-stage diagnosis, high recurrence rates, and the development of chemoresistance. Although targeted therapies have improved patient outcomes, their efficacy is often limited by off-target toxicity and acquired drug resistance. Extracellular vesicles (EVs), nanoscale vesicles naturally released by cells, have emerged as promising carriers for precision drug delivery. This review provides a comprehensive overview of recent advances in EV-based therapeutic strategies for ovarian cancer, including the delivery of chemotherapeutic agents, nucleic acid therapeutics, and immunomodulatory molecules. We further explore innovative engineering approaches to enhance targeting specificity, such as surface modification, cell source selection, biomaterial integration, and magnetic nanoparticle-assisted delivery. Key translational challenges in bringing EV-based therapies to clinical application are also addressed. Collectively, these insights underscore the transformative potential of EV-based platforms in advancing targeted and personalized treatment for ovarian cancer.

Abstract In sepsis, the liver functions as a central filter organ, where hepatic macrophages form a primary antimicrobial defense layer by eliminating bacteria and regulating immune responses. Therefore, precise regulation of the immune response in hepatic macrophages is crucial for triggering effective defense mechanisms. We aim to modulate the defense immune response by delivering transcription factor HIF1α, a key regulator of monocyte/macrophage reprogramming in sepsis. Transcription factors are promising candidates because they dynamically modulate gene expression across diverse conditions, though delivering them remains challenging. In this study, we suggest a novel method for loading HIF1α into extracellular vesicles (EVs) to enhance immune defense and resolve sepsis. By delivering HIF1α to macrophages during sepsis, we promoted the differentiation of Nr1h3-dependent pro-efferocytic MoMFs and C/ebpβ-dependent pro-survival MoMFs. Pro-efferocytic MoMFs eliminate damaged hepatocytes and immune cells and pro-survival MoMFs withstand inflammatory conditions and trigger innate memory responses. Particularly, the zonation of these macrophages in the periportal region ensures effective pathogen clearance and minimizes tissue damage. These findings suggest that EV-mediated HIF1α delivery could be a promising therapeutic option for managing sepsis.

Delivery of secretomes, which includes growth factors, cytokines, and mRNA, is critical in regenerative medicine for cell-to-cell communication. However, the harsh in vivo environment presents significant challenges for secretome delivery. Proteolytic enzymes shorten secretomes' half-lives, and secretomes tend to rapidly diffuse at defect sites. Therefore, a delivery system that ensures prolonged retention and enhanced therapeutic efficacy of secretomes is required. In this study, a Coating Optimized Drug Delivery Enhancement (COD₂E) system, a coacervate composed of dopamine functionalized fucoidan and poly-l-lysine, was fabricated for secretome delivery. The dopamine modification significantly enhanced adhesive strength (>7-fold) compared to that of the neat coacervates, which enabled rapid (5 min) and uniform coating ability on collagen sponges. The COD₂E system was able to encapsulate fibroblast growth factor (FGF2) and prolong the half-life of FGF2. Notably, its efficacy, demonstrated through a single application of FGF2 encapsulated COD₂E on collagen sponge, in a wound model demonstrated a successful tissue repair. The COD₂E system is an effective growth factor delivery vehicle since it can protect growth factors, has an antioxidant ability, adheres on various material surfaces, and is hemocompatible.

TMEM158 is highly expressed in lung cancer, is associated with hypoxia, and promotes EMT and cell migration. These findings suggest TMEM158 as a potential target for lung cancer therapies.