Melatonin–selenium nanoformulation: a promising therapeutic strategy against Ehrlich ascites carcinoma

www.nature.com/scientificreports OPEN Melatonin–selenium nanoformulation: a promising therapeutic strategy against Ehrlich ascites carcinoma Hanaa M. Morad, A. F. Abdel-Aziz & Mai M. Madkour Combination therapy has emerged as a standard strategy for enhancing the efficacy of anticancer treatments. The purpose of our study was to assess the melatonin-selenium nanoparticles’ anticancer potential (MSeNPs) in a murine model of Ehrlich ascites carcinoma (EAC). Assessments included cell viability, hematological parameters, oxidative stress markers, apoptosis, cell cycle dynamics, and pro-inflammatory cytokines. Our findings demonstrate that MSeNPs inhibit tumor growth and enhance antioxidant defenses. MSeNPs significantly reduce IL-6 levels, alleviating EAC-associated inflammation. Furthermore, MSeNPs induced apoptosis through caspase-3 activation and Ki-67 downregulation, resulting in decreased cell proliferation and significant G0/G1 cell cycle arrest, accompanied by marked suppression of the S phase. In conclusion, these results highlight the synergistic therapeutic advantage of MSeNPs, indicating greater efficacy than monotherapies with melatonin, selenium, or selenium nanoparticles alone. MSeNPs hold promise as a potent, multitargeted agent for future cancer therapies. Keywords Melatonin-selenium nanoparticles, Ehrlich ascites carcinoma, Oxidative stress, Inflammation, Apoptosis, Cell cycle Abbreviations EAC Ehrlich ascites carcinoma MEL Melatonin Se Selenium ROS Reactive oxygen species SeNPs Selenium nanoparticles NOAELs No observed adverse effect levels LOAELs Lowest observed adverse effect levels MSeNPs Melatonin-selenium nanoparticles SEM Scanning electron microscope TEM Transmission electron microscope EDX Energy dispersive X-ray Hb Hemoglobin RBCs Red blood cells WBCs White blood cells CAT Catalase SOD Superoxide dismutase GPX Glutathione peroxidase MDA Malondialdehyde NO Nitric oxide IL-6 Interleukin-6 H&E Hematoxylin and eosin SE Standard error Department of Chemistry, Faculty of Science, Mansoura University, Mansoura 35516, Egypt. ; Scientific Reports | (2026) 16:16264 | https://doi.org/10.1038/s41598-026-53359-w email: 1 It is well known that cancer is a potentially fatal disease characterized by abnormal and uncontrolled cell proliferation in any organ or tissue of the body. Treatments for cancer vary based on the type and stage of the disease and include clinical approaches such as surgery, radiotherapy, stem cell therapy, chemotherapy, immunotherapy, hormonal therapy, and targeted medications. Additionally, various products have shown promising potential in the prevention and treatment of cancer1. Despite this, the high cost of anticancer therapies and their detrimental adverse effects, along with the significant challenge of discovering effective drugs that can target various types of cancer, highlight the urgent need to develop new and more effective therapies2. The Ehrlich ascites carcinoma (EAC) mouse model is a well-known, rapidly proliferating, and highly reproducible transplantable tumor type that is frequently used for the preliminary evaluation of anticancer drugs. After intraperitoneal injection, the ascitic form develops. Tumor-induced inflammation and increased peritoneal vascular permeability led to ascites accumulation. This model is particularly useful for evaluating therapeutic efficacy, as it closely mimics aggressive tumor behavior3. Nanotechnology, a promising new approach, has attracted increasing attention in cancer therapy research due to its potential to improve treatment outcomes4. Nanoparticles typically range in size from 10 to 100 nanometers and possess a large surface area, making them highly suitable for various biological applications. Due to their small size, nanomaterials can easily travel throughout the body, moving between organs and effectively penetrating targeted tissues. For both therapeutic and diagnostic applications, they can also be coupled with pharmacological molecules to target diseased tissues, such as cancer cells. Notably, nanoparticles are comparable in size to DNA and smaller than blood cells, which improves their capacity to interact at the molecular level5. Melatonin (MEL), also known as N-acetyl-5-methoxytryptamine, is a naturally occurring hormone synthesized by various tissues in the human body. Although the pineal gland is the primary site of production, other tissues, including the bone marrow, retina, gastrointestinal tract, and lymphocytes, also synthesize it6. As a potent antioxidant, MEL effectively scavenges free radicals and inhibits oxidative stress in both in vitro and in vivo settings7. MEL is a lipophilic compound with a broad spectrum of biological anticancer effects, including notable anti-angiogenic properties8, as well as anti-migration, anti-invasion9, pro-apoptotic10, and anti-proliferative activities11. There is growing interest in the wide application of MEL for the treatment of various diseases, including inflammatory conditions, gastrointestinal disorders, cancer, mood disorders, and others6. MEL has demonstrated anticancer effects in several types of malignancies, including lung, cervical, gastric, breast, and colorectal cancers12. A possible interaction between micronutrient status and MEL-mediated biological effects is suggested by the important roles that trace elements like zinc, selenium, and magnesium play in enzymatic and antioxidant systems that are directly linked to MEL biosynthesis and activity13. The trace element selenium (Se) is necessary for numerous biological functions. Specifically, at least 25 human selenoproteins, which are involved in a wide range of essential biological activities, include the amino acid selenocysteine, also known as the 21st amino acid. These include the regulation of reactive oxygen species (ROS), thyroid hormone metabolism, and immune function. Consequently, Se plays a critical role in modulating and preventing the clinical outcomes of various diseases, including cancer, diabetes, Alzheimer’s disease, mental health disorders, cardiovascular diseases, fertility issues, inflammatory conditions, and infections14. Se exists in both organic and inorganic forms; however, these forms exhibit limited absorption in the gastrointestinal tract and, more importantly, may exert toxic effects at high doses. These limitations have driven interest in the development of selenium nanoparticles (SeNPs), which aim to improve bioavailability and reduce toxicity, offering a safer and more efficient alternative for therapeutic and nutritional applications15. Compared to traditional Se compounds, such as sodium selenate and sodium selenite, SeNPs demonstrate lower toxicity and greater biocompatibility, making them a safer and more effective option for therapeutic use16. Because of their distinct physicochemical characteristics, SeNPs have become an effective option for the clinical use of Se. These characteristics include hig (...truncated)