Milk-Derived Extracellular Vesicle-Coated ZIF-90 Nanoparticles for pH-Responsive Doxorubicin Delivery in Prostate Cancer Cells

Articles in Press

Document Type : Research Articles

Authors

Mehrdad Aghasizadeh

Ahmadreza Bahrami

Maryam M. Matin

Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran

10.22067/jcmr.2026.100839.1141

Abstract

Prostate cancer remains a major cause of cancer-related morbidity and mortality in men, while the clinical use of doxorubicin (DOX) is still limited by systemic toxicity and poor tumor selectivity. Here, a pH-responsive ZIF-90 metal-organic framework was synthesized as a DOX nanocarrier and coated with milk-derived extracellular vesicles (mEVs) to produce a biomimetic delivery platform, mEV@ZIF-90@DOX. The physicochemical properties, drug release behavior, and in vitro anticancer activity of the nanoparticles were consequently evaluated against PC-3 prostate cancer cells. The nanoparticles displayed a polyhedral morphology, an average size of 84 nm, and a drug encapsulation efficiency of 74.0 ± 1.8%. Drug release was pH-dependent, with markedly greater cumulative DOX release at pH 5.5 than at pH 7.4. All formulations produced concentration- and time-dependent cytotoxicity in PC-3 cells; DOX loading into ZIF-90 initially lowered cytotoxicity relative to free DOX, but mEV coating restored and ultimately exceeded this activity after prolonged incubation, giving the lowest IC₅₀ (3.50 μg/mL) at 72 h. Flow cytometry after annexin V-FITC/PI staining confirmed this trend, with mEV@ZIF-90@DOX producing the highest total apoptotic fraction (95.6%, both early and late apoptosis), compared with free DOX (91.5%) and uncoated ZIF-90@DOX (83.7%), while necrosis remained negligible in all groups. These results indicate that mEV coating improves the therapeutic performance of ZIF-90-based DOX carriers, supporting their potential as a biomimetic platform for prostate cancer treatment. Further investigations are required to evaluate the pharmacokinetics, biodistribution, and antitumor efficacy of this nanoplatform in animal prostate cancer models before clinical translation into practice can be considered.

Keywords

ZIF-90

Doxorubicin

Milk-derived extracellular vesicles

Prostate cancer

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