Search Results (10,260)

Oral wound healing is a robust process; however, complications from surgery, systemic diseases, and aging can impair healing. While some treatments exist, regenerative therapies to promote mucosal wound healing remain limited. In recent years, there has been a significant rise in FDA-approved cell-based therapies; however, extracellular vesicles represent an emerging cell-free alternative that may mitigate risks associated with cellular therapies, including tumorigenesis and immunogenicity. These lipid-encapsulated nanovesicles can deliver therapeutic cargo, such as proteins, lipids, nucleic acids, or drugs, to the wound site. Extracellular vesicles can be derived from mesenchymal stromal cells, immune cells, bodily fluids, or bacteria, and engineered through genetic modification, preconditioning, or direct cargo loading to enhance therapeutic potency. Furthermore, advanced delivery platforms, including hydrogels, microneedles, and aerosols, allow for sustained and localized EV delivery to the oral wound site. This review examines differences between cutaneous and oral wound healing; factors that impair oral repair; extracellular vesicle sources and engineering strategies; and delivery strategies for developing EV-based therapeutics for oral wound healing. Full article

Pancreatic β-cell replacement represents a promising therapeutic avenue for insulin-dependent diabetes, yet clinical translation has been limited by donor scarcity, immune rejection, and incomplete engraftment. Three-dimensional (3D) pancreatic organoids derived from human pluripotent stem cells (hPSCs) or primary tissue offer a scalable and physiologically relevant platform, recapitulating native islet architecture, paracrine interactions, and glucose-responsive insulin secretion. Recent advances in differentiation protocols, vascularization strategies, and immune-protective approaches—including encapsulation and hypoimmunogenic engineering—have enhanced β-cell maturation, survival, and functional performance in vitro and in vivo. Despite these developments, challenges remain in achieving fully mature β-cells, durable graft function, and scalable, reproducible production that is suitable for clinical use. This review highlights the promise of pancreatic organoid engineering, emphasizing strategies to optimize β-cell maturation, vascular integration, and immune protection, and outlines key future directions to advance organoid-based β-cell replacement toward safe, effective, and personalized diabetes therapies. Full article

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease, marked by progressive degeneration of upper and lower motor neurons. Clinically, genetically, and pathologically heterogeneous, ALS poses a major challenge for disease modeling and therapeutic translation. Over the past two decades, induced pluripotent stem cells (iPSCs) have reshaped our understanding of ALS pathogenesis and emerged as a promising translational platform for therapy development. ALS modeling has further expanded with the advent of three-dimensional systems, including ALS-on-chip platforms and organoid models, which better capture cell–cell interactions and tissue-level phenotypes. Despite these advances, effective disease-modifying therapies remain elusive. Recent clinical trial setbacks highlight the need for improved trial design alongside robust, translational iPSC models that can better predict therapeutic response. Nonetheless, the outlook is promising as large iPSC patient cohorts, quantitative phenotyping combined with genetically informed patient stratification, and reverse translational research are beginning to close the gap between in vitro discovery and clinical testing. In this review, we summarize the major advances in iPSC technology and highlight key iPSC-based studies of sporadic ALS. We further discuss emerging examples of iPSC-informed therapeutic strategies and outline the challenges associated with translating iPSC-derived mechanistic insights and pharmacological findings into successful clinical therapies. Full article

Background: Follicular lymphoma (FL) is the second most common B-cell lymphoma in Western countries, typically presenting as an indolent disease with prolonged overall survival. Despite favorable initial responses to therapy, most patients experience relapse, and early progression is associated with poor outcomes. Methods: This guideline provides evidence-based recommendations from the Spanish GELTAMO group on the diagnosis, staging, treatment, and follow-up of FL. A systematic literature review was conducted, and recommendations were graded according to the GRADE system. Results: Histopathological diagnosis should be based on excisional biopsy. PET-CT is recommended for staging and response evaluation. For localized disease, involved-site radiotherapy (ISRT) remains the treatment of choice. In asymptomatic patients with advanced-stage disease and low tumor burden, a watch-and-wait approach is appropriate, although rituximab monotherapy is also acceptable. For advanced-stage disease with high tumor burden, immunochemotherapy with anti-CD20 antibodies (rituximab or obinutuzumab) combined with CHOP, CVP, or bendamustine is recommended, followed by maintenance therapy. Management of relapsed disease is tailored based on tumor burden, treatment history, and timing of relapse. Although novel immunotherapies (CAR-T therapy and bispecific antibodies) are emerging as promising options, autologous stem cell therapies may still be a valid option in young patients with early relapse who are sensitive to immunochemotherapy. Conclusions: FL is a heterogeneous disease requiring individualized management strategies. Recent advances in immunotherapy and molecular diagnostics are reshaping the therapeutic landscape. These updated GELTAMO recommendations aim to provide practical guidance for optimal FL management in clinical practice. Full article

Background/Objectives: Hydroxyurea is currently the standard disease-modifying therapy for reducing sickle cell disease (SCD) complications; however, drug labels currently advise discontinuation of breastfeeding during hydroxyurea therapy due to limited human data on the risk of hydroxyurea exposure in breastfed neonates. Methods: A physiologically based pharmacokinetic (PBPK) model for hydroxyurea was built and verified with data from non-lactating adult patients with SCD. The model was then extended to predict hydroxyurea in nursing and in paediatric populations. Predictions were compared to the observed data. Results: The PBPK model predictions for hydroxyurea pharmacokinetics described the observed data in both adult and paediatric subjects with SCD. Observed concentration profiles were within the 5th–95th prediction intervals, and predicted PK parameters were within 2-fold of the observed values. The predicted milk-to-plasma ratio was 0.8. Neonatal exposure to hydroxyurea via breast milk as a percentage of maternal exposure increased from 0.6% at 1 day to 10% at the 4th week postpartum before declining to 5%, 3%, and 2% at 6, 9, and 12 months postpartum, respectively. Conclusions: About 56% of total milk hydroxyurea exposure is within the first 3 h of post-maternal dose. Disposal of this early milk would reduce the exposure of breastfed children. The reduction in exposure is especially pronounced around the first 1 month postpartum. Lactation PBPK models offer a physiological approach to assess real-life scenarios that are difficult to investigate in clinical studies and provide useful results for future clinical study design and clinical recommendations. This was exemplified with hydroxyurea in the current work. Full article

Cancer remains a leading global cause of death, with conventional treatments often limited by toxicity and recurrence. Recent advances in gene therapy and nanodrug delivery offer new avenues for precision oncology. Human telomerase reverse transcriptase (hTERT) and glutathione peroxidase 4 (GPX4) are overexpressed in many cancers and linked to apoptosis and ferroptosis, respectively. Here, we developed a manganese dioxide nanosheet (MnO₂-NS) probe co-loaded with antisense oligonucleotides targeting hTERT and GPX4 mRNA to synergistically down-regulate both genes and induce dual cell death pathways. The probe, assembled via adsorption of fluorescently labeled antisense strands, showed controllable release in the presence of glutathione (GSH). Cellular uptake and antisense release were confirmed in multiple cancer cell lines. The MnO₂-NS probe significantly suppressed cell proliferation, outperforming single-target or carrier-only controls. Molecular analyses confirmed reduced hTERT and GPX4 expression, along with GSH depletion, ROS accumulation, and elevated lipid peroxidation—collectively promoting enhanced cancer cell death. In summary, this MnO₂-NS-based co-delivery system enables synergistic gene silencing and GSH depletion, enhancing antitumor efficacy and providing a promising strategy for multifunctional nanotherapy. Full article

Circulating tumor cells (CTCs) are shed from the primary tumor into the bloodstream and represent dynamic molecular biomarkers for monitoring the progression of cancer. While profiling tumor tissues with over expression of cell surface markers, such as PD-L1 or HER2, is standard in guiding therapy, tissue samples are often inaccessible and inadequate, especially post-surgery or in cases of recurrence. Emerging clinical evidence indicates that CTC counts and biomarker surface expression can predict prognosis and therapeutic resistance more accurately than imaging or tissue-based approaches. Recent advancements in the CTC detection methods, based on physical properties or surface markers (e.g., EpCAM), coupled with next-generation sequencing (NGS) have enabled the isolation of these rare cells and their molecular characterization. Consequently, CTCs provide a real-time alternative, enabling repeated, longitudinal assessment of tumor phenotype and therapeutic response. This review emphasizes the translational potential of surface protein biomarkers on CTCs for profiling, namely PD-L1, HER2, and EGFR, as a clinically actionable approach to stratify patients, guide immunotherapy decisions, and monitor minimal residual disease (MRD), especially when longitudinal tissue biopsies are not feasible. Full article

Carbon dots (CDs) have emerged as a promising non-viral gene delivery vector due to their excellent biocompatibility and tunable surface properties. In this study, four CDs with gradient-positive zeta potentials (7.23 mV, 16.7 mV, 25.3 mV, 34.5 mV) were synthesized via a hydrothermal method. Among these, CDs-3 with an optimal zeta potential of 25.3 mV stood out, exhibiting ultra-low cytotoxicity (cell viability >80% even at 50 μg/mL) and a transfection efficiency of nearly 100% (for GFP plasmid delivery), significantly outperforming commercial vectors Lipo2000 and PEI. A stable CDs-3/siIhh delivery system was constructed at a mass ratio of 2:1. In vitro evaluations confirmed that CDs-3/siIhh could efficiently regulate the Indian Hedgehog (Ihh) signaling pathway and osteoarthritis (OA)-related markers in both normal and IL-1β-induced inflammatory ATDC5 chondrocytes. Its regulatory effect was significantly superior to that of the commercial Lipo2000/siIhh and PEI/siIhh systems. This consistent “transcription–translation” regulation, combined with the carrier’s safety and excellent cellular internalization capacity in chondrocytes, highlights its potential for OA gene therapy. Collectively, our work develops a novel, safe, and efficient positive-potential CD-based gene delivery vector, providing a promising gene regulatory capacity by leveraging optimized surface charge engineering. Full article

NK cells are key components of the innate immune system, capable of recognizing and eliminating tumor or virus-infected cells and able to modulate both innate and adaptive immune responses. This makes NK cells attractive candidates for cancer immunotherapy, through passive approaches such as adoptive NK cell transfer, or active approaches aimed at enhancing endogenous NK cell activity in vivo. Promising results have emerged from preclinical studies and early-phase clinical trials. Nevertheless, the therapeutic efficacy of NK cell-based approaches is often limited by several factors, such as the poor NK cell persistence in vivo, the inefficient tumor infiltration, and the immunosuppressive milieu typical of the tumor microenvironment. The preclinical development of NK cell-based therapies relies largely on animal models. Humanized mouse models have evolved from early immunodeficient strains to more advanced systems incorporating human cytokines, which more effectively support NK cell development, maturation, and function. These models have substantially improved our understanding of human NK cell biology and enabled the evaluation of novel therapeutic strategies. However, further optimization is still required to better recapitulate the tissue-specific heterogeneity of human NK cells and their conditioning by the tumor microenvironment. In this review, we provide an overview of recent advances in the generation of humanized mouse models for NK cell-based cancer immunotherapy, discussing their advantages and limitations and highlighting how emerging technologies may contribute to the development of more predictive preclinical platforms. Full article

B7-H3 (CD276), a member of the B7 family of proteins, is known to play a key role in the progression of a number of cancers. This protein is selectively expressed in both tumor cells and immune cells within the tumor microenvironment. Various investigations, including a number of clinical trials, have reported high levels of expression of this protein in cancerous tissues compared to their healthy counterparts. This difference in expression attracted various research efforts to establish whether such a difference can be linked to the therapeutic potential of this molecule. It is worth noting that B7-H3 is not the only immune checkpoint expressed at different levels in cancerous and healthy cells. Therapeutic strategies, based on different levels of expression, have been tested with other checkpoints. To inhibit the expression of some checkpoints, immune checkpoint inhibitors (ICIs) were developed. The introduction of these inhibitors for the treatment of some forms of advanced-stage tumors has been justly described as an important milestone in the landscape of immune therapy. Years after the launch of these inhibitors, numerous clinical trials revealed that these inhibitors benefit a narrow subset of patients suffering from advanced-stage tumors, while the majority of patients treated with these inhibitors either did not respond positively or simply did not respond at all (refractory patients). Other clinical trials showed that this form of treatment can provoke serious immune-related adverse events (irAEs). It is fair to state that changes in the expression level of a given protein in diseased tissue is an important parameter to take into account in the assessment of such a protein as a therapeutic target. However, the last ten years have demonstrated that taking the level of expression of a given checkpoint within a cancerous tissue is not sufficient to consider such expression a reliable predictive biomarker for the investigated disease. On the other hand, to establish a solid base for a given therapeutic strategy, these varying levels of expression have to be combined with a deep understanding of the biology of the molecule under investigation, as well as the identification and thorough analysis of the relevant signaling pathways, particularly those communicating with both the investigated molecule and the immune system. Recently, a number of pharmaceutical and biotechnology firms have suggested that B7-H3 is a highly promising therapeutic target for the development of immune therapeutics. In this review, we ask why hopes of better therapeutic performance are attached to this immune checkpoint. A partial answer to this question is provided through the careful consideration of the available data generated by various clinical trials. The contribution of mass spectrometry-based proteomics to this area of research is highlighted. Full article

In recent years, remarkable progress in nanomedicine has been achieved, leading to the development of several nanocarriers which aim to enhance the therapeutic efficacy in cancer treatment. Owing to their high versatility and highly tunable physicochemical properties, alumina (Al₂O₃) and silica (SiO₂) substrates represent promising and innovative nanoplatforms that are widely used in biomedical applications, such as drug-delivery, diagnosis, and biosensing in cancer. In particular, such platforms possess multiple advantageous properties, including mechanical stability, high loading capacity, tunable porosity, excellent biocompatibility, and in vitro and in vivo low toxicity. In this review article, we discuss their emerging role as biosensing platforms and drug delivery systems in oncology. As such, we describe how these substrates enable the incorporation of antibodies against various cancer biomarkers [e.g., cancer antigen 15-3 (CA15-3), serum amyloid A1 (SAA1), epithelial cell adhesion molecule (EpCAM), or human epidermal growth factor receptor 2 (HER2)] for the detection of multiple malignancies. Furthermore, we highlight the development of highly promising alumina- and silica-based platforms for drug delivery (e.g., chemotherapeutics, photosensitizers, or gene delivery agents) in cancer. Ultimately, by providing a comprehensive overview alongside a critical analysis, we demonstrate that such nanostructures represent promising platforms for potential clinical translation in cancer medicine, helping to mitigate the limitations of conventional cancer therapies. Full article

Diabetic retinopathy (DR) remains the leading cause of preventable blindness among working-age adults worldwide, driven by the growing prevalence of diabetes mellitus. The aim of this comprehensive literature review is to provide an insightful analysis of recent advances in the pathogenesis of DR, followed by a summary of emerging technologies for its diagnosis and treatment. Recent studies have explored the roles of cell death pathways, immune activation, and lipid peroxidation in the pathology of DR. However, at the core of DR pathology lies neovascularization driven by vascular endothelial growth factor (VEGF), and mitochondrial damage due to dysregulated oxidative stress. These dysregulated pathways manifest clinically as DR, with specific subtypes including non-proliferative DR, proliferative DR and diabetic macular edema, which can be diagnosed through various imaging modalities. Recently, novel advances have been made using liquid biopsy and artificial (AI)-based algorithms with the goal of transforming DR diagnostics. AI models show distinct promise with the capacity to provide automated interpretation of retinal imaging. Furthermore, conventional anti-VEGF injectable agents have revolutionized DR treatment in the past decades. Today, as the pathogenesis of DR becomes better understood, new pathways, such as the ROS-VEGF loop, are being elucidated in greater depth, enabling the development of targeted therapies. In addition, new innovations such as intravitreal implants are transforming the delivery of DR-specific medication. This paper will discuss the current understanding of the pathogenesis of DR, which is leading to new diagnostic and therapeutic tools that will transform clinical management of DR. Full article

Cardiac transplantation remains an important therapy for end-stage heart failure, although allograft rejection continues to pose significant clinical challenges. This review evaluates both established and emerging blood-based biomarkers for noninvasive monitoring of rejection in heart transplant recipients. Donor-derived cell-free DNA (ddcfDNA) and gene expression profiling (GEP) represent well-validated, commercially available molecular tools that demonstrate strong discriminative capacity for acute rejection episodes. Additionally, microRNAs (miRs) and extracellular vesicles (EVs) show considerable potential as novel biomarkers, although further validation is required. In contrast, conventional biomarkers such as B-type natriuretic peptide (BNP), cardiac troponins, and creatine kinase-MB (CK-MB) offer limited specificity in the context of rejection. This review synthesizes current evidence on the clinical utility, methodological challenges, and integration strategies of these biomarkers, highlighting a shift toward molecular-based approaches for improving post-transplant surveillance and patient outcomes. Full article

The growing prevalence of multidrug-resistant (MDR) Candida spp. necessitates the development of new antifungal strategies. Photodynamic therapy (PDT), already widely used in the treatment of various oral infections, is based on the synergistic interaction of three key elements: a photosensitizer capable of selectively binding to microbial cells, a light source with the appropriate wavelength, and the presence of molecular oxygen. This interaction results in the production of singlet oxygen and reactive oxygen species, responsible for the selective destruction of microorganisms. In recent years, numerous natural compounds have been explored as potential photosensitizers. Olive oil, a cornerstone of the Mediterranean diet, was recently recognized by the U.S. Food and Drug Administration as a medicinal substance thanks to its soothing, immunomodulatory, and antimicrobial properties, which have also been documented in regard to oral administration. Materials and Methods: The aim of this in vitro study was to evaluate the efficacy of activated olive oil as a novel photosensitizer in PDT against Candida species. Oral MDR clinical isolates of C. albicans, C. krusei, and C. glabrata were analyzed using the Kirby–Bauer method according to EUCAST protocols. Six different experimental conditions were considered for each strain: (i) 100 μL of extra-virgin olive oil (EVOO); (ii) 100 μL of EVOO pre-activated with 3% H₂O₂ (EVOO-H); (iii) 100 μL of EVOO irradiated for 5 min with polarized light (480–3400 nm, 25 W); (iv) 100 μL of EVOO-H subjected to the same polarized light; (v) 100 μL of EVOO irradiated for 5 min with a 660 nm diode laser (100 mW); and (vi) 100 μL of EVOO-H irradiated with the same laser. All plates were incubated at 37 °C for 48 h. Results: The results showed a variable response among the different Candida species. C. glabrata showed sensitivity to all experimental conditions, with a 50% increase in the diameter of the inhibition zone in the presence of polarized light. C. krusei showed no sensitivity under any of the conditions tested. C. albicans showed antifungal activity exclusively when EVOO-H was activated by light. In particular, activation of EVOO and EVOO-H with polarized light resulted in the largest inhibition zones. Conclusions: In conclusion, olive oil, both alone and pre-activated with hydrogen peroxide, can be considered an effective photosensitizer against drug-resistant Candida spp., especially when combined with polarized light. Full article

Glioblastoma multiforme (GBM) is characterized by aggressive growth, extensive vascularization, high metabolic malleability, and a striking capacity for therapy resistance. Current treatments involve surgical resection and concomitant radiation therapy and chemotherapy, prolonging survival times marginally due to the therapy resistance that is built up by the tumor cells. A growing body of research has identified exosomes as critical enablers of therapy resistance. These nanoscale vesicles enable GBM cells to disseminate oncogenic proteins, nucleic acids, and lipids that collectively promote angiogenesis, maintain autophagy under metabolic pressure, and suppress apoptosis. As interest grows in targeting tumor communication networks, exosome-based therapeutic strategies have emerged as promising avenues for improving therapeutic outcomes in GBM. This review integrates current insights into two complementary therapeutic strategies: inhibiting exosome biogenesis and secretion, and engineering exosomes as precision vehicles for the delivery of anti-tumor molecular cargo. Key molecular regulators of exosome formation—including the endosomal sorting complex required for transport (ESCRT) machinery, tumor susceptibility gene 101 (TSG101) protein, ceramide-driven pathways, and Rab GTPases—govern the sorting and release of factors that enhance GBM survival. Targeting these pathways through pharmacological or genetic means has shown promise in suppressing angiogenic signaling, disrupting autophagic flux via modulation of autophagy-related gene (ATG) proteins, and sensitizing tumor cells to apoptosis by destabilizing mitochondria and associated survival networks. In parallel, advances in exosome engineering—encompassing siRNA loading, miRNA enrichment, and small-molecule drug packaging—offer new routes for delivering therapeutic agents across the blood–brain barrier with high cellular specificity. Engineered exosomes carrying anti-angiogenic, autophagy-inhibiting, or pro-apoptotic molecules can reprogram the tumor microenvironment and activate both the intrinsic mitochondrial and extrinsic ligand-mediated apoptotic pathways. Collectively, current evidence underscores the potential of strategically modulating endogenous exosome biogenesis and harnessing exogenous engineered therapeutic exosomes to interrupt the angiogenic and autophagic circuits that underpin therapy resistance, ultimately leading to the induction of apoptotic cell death in GBM. Full article