In this study, a bovine serum albumin-decorated zeolitic imidazolate framework (ZIF-8@BSA) was used to enhance the anticancer and antimetastatic properties of methotrexate. SEM, DLS, FT-IR, and XRD confirmed the physicochemical suitability of the developed nanoparticles. According to the SEM analysis, the mean size of ZIF-8 nanoparticles was 68.5 ± 13.31 nm. The loading capacity and encapsulation efficiency of MTX@ZIF-8@BSA were 28.77 ± 2.54% and 96.3 ± 0.67%, respectively. According to the hemolysis test, MTX@ZIF-8@BSA showed excellent blood compatibility. MTX@ZIF-8@BSA exhibited pH sensitivity, releasing more MTX at pH 5.4 (1.73 times) than at pH 7.4. The IC value of MTX@ZIF-8@BSA on 4T1 cells was 32.7 ± 7.3 µg/mL after 48 h of treatment, outperforming compared to free MTX with an IC value of 53.3 ± 3.7 µg/mL. Treatment with MTX@ZIF-8@BSA resulted in superior tumor growth suppression in tumor-bearing mice than free MTX. Furthermore, based on histopathology tests, MTX@ZIF-8@BSA reduced the metastasis in lung and liver tissues. While there was not any noticeable toxicity in the vital organs of MTX@ZIF-8@BSA-receiving mice, free methotrexate resulted in severe toxicity in the kidneys and liver. According to the preliminary and findings, MTX@ZIF-8@BSA presents an attractive drug delivery system candidate for breast cancer due to its enhanced antitumor efficacy and lower toxicity.
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