FA-PEG Modified ZIF(Mn) Nanoparticles Loaded with Baicalin for Imaging-Guided Treatment of Melanoma in Mice

Dong Zhang, Mogen Zhang, Huiping Fan, Rui Sun, Jiayun Liu, Weiyuan Ma Department of Dermatology, Affiliated Hospital of Shandong Second Medical University, School of Clinical Medicine, Shandong Second Medical University, Weifang, 261031, People’s Republic of ChinaCorrespondence: Weiyuan Ma, Email [email protected]: Melanoma is an aggressive skin tumor with limited therapeutic options due to rapid proliferation, early metastasis, and poor prognosis. Baicalin (BA), a natural flavonoid, shows promise in inducing ferroptosis and apoptosis but faces challenges of poor solubility and bioavailability. To address these issues, we developed a multifunctional drug delivery system: manganese-doped ZIF-8 nanoparticles (ZIF(Mn)) loaded with BA and modified with folic acid (FA) and polyethylene glycol (PEG). FA targets melanoma cells by exploiting folate receptor overexpression, while PEG enhances biocompatibility and systemic circulation. Manganese enables magnetic resonance (MR) imaging for real-time, non-invasive therapy monitoring.Methods: BA-loaded ZIF(Mn)/FA-PEG nanoparticles were synthesized via a one-pot method, enabling drug encapsulation, Mn²+ incorporation, and surface modification. The nanoparticles were comprehensively characterized (particle size, Zeta potential, FTIR, and XRD). Cytotoxicity and cellular uptake were evaluated in B16-F10 melanoma cells, and in vivo experiments in C57BL/6J mice investigated MR imaging capability, antitumor efficacy, and biosafety.Results: BA@ZIF(Mn)/FA-PEG nanoparticles demonstrated excellent stability, a BA loading capacity of 33.50 ± 0.04%, and pH-responsive release, with accelerated drug release under acidic tumor conditions. Mn²+ provided strong T1-weighted MR imaging contrast. Cellular and animal studies showed enhanced uptake, reduced premature drug release, and improved compatibility. Mechanistically, the nanoparticles induced significant ferroptosis and apoptosis in melanoma cells, leading to potent antitumor effects.Conclusion: The BA@ZIF(Mn)/FA-PEG nanoplatform effectively integrates targeted delivery, imaging guidance, and dual ferroptosis-apoptosis induction, offering a promising strategy for improving melanoma treatment outcomes.Keywords: Baicalin, melanoma, metal−organic frameworks, folic acid targeted, magnetic resonance imaging, ferroptosis