Tabriz University of Medical Sciences Advanced Pharmaceutical Bulletin 2228-5881 16 2 2026 06 15 Design, Characterization, and In-Vitro Targeted Delivery of Melatonin via pH-Responsive Niosome Nanoparticles Decorated with Folate Against Colon Cancer Cells 377 386 10.34172/apb.46393 EN Davoud Jafari-Gharabaghlou https://orcid.org/0000-0002-4878-5009 Urjwan Alali Fadhil Jawad Al-Tu’ma Hamid Babavalian Mozafar Mohammadi Mohammad Sadegh Hashemzadeh https://orcid.org/0000-0003-3524-1798 Journal Article 10.34172/apb.46393 2025 09 18 2026 05 07 Introduction: Utilizing targeted drug delivery in oncology represents a valuable strategy to enhance the therapeutic efficacy of chemotherapy and simultaneously mitigate its adverse effects. Our present investigation focused on harnessing the therapeutic properties of melatonin as an anti-cancer agent and improving its bioavailability by employing a drug delivery system based on folic acid-decorated niosomal nanoparticles. Methods: To deliver melatonin, a niosomal and a folic acid decorated niosomal system was used. Nanoparticles were synthesized with the thin film hydration method and characterized by AFM, SEM, DLS, and FT-IR techniques. The cytotoxic effects and changes in gene expression were assessed using MTT and real-time PCR techniques, respectively. Additionally, flow cytometry experiments were conducted to investigate their impact on cell cycle arrest and apoptosis induction. Results: Nanoparticle analysis revealed that the size distribution of blank niosomes, melatonin-loaded niosomal nanoparticles, and melatonin-loaded folic acid-decorated niosomal nanoparticles were 157±8.96 nm, 198±12.34 nm, and 239.9±39.64 nm, respectively. Controlled release studies indicated that over 96 hours, the maximum amount of melatonin released was approximately 60% at pH 7.4 and 73% at pH 5. The results demonstrated enhanced cell cytotoxicity of melatonin when encapsulated in melatonin-loaded folic acid-decorated niosomal compared to pure melatonin and niosomal nanoparticles. Furthermore, melatonin-loaded folic acid-decorated niosomal nanoparticles exhibited superior outcomes in terms of promoting apoptosis and cell cycle arrest compared to other tested substances. Conclusion: Overall, melatonin-loaded folic acid-decorated niosomal nanoparticles demonstrate a significant capability as an effective therapeutic strategy for targeting colorectal cancer cells.