**4. Conclusions**

In the current study, ß-CD nanosponges cross-linked with diphenyl carbonate were selected for improving the bioavailability and anticancer potential of fisetin. For the first time, to the best of our knowledge, FS-NS was coated with the active targeting ligand LF (LF-FS-NS). The optimized formulations of FS-NS and LF-FS-NS were shown to enhance FS bioavailability both orally and via IP injection. NS formulations administered by IP significantly enhanced the efficacy of FS against breast cancer. This was verified at both the cellular level on MDA-MB-231 cells and the molecular level in an Ehrlich ascites tumor compared to FS suspension, with superior effects achieved by the actively targeted formulation (LF-FS-NS). Accordingly, LF-FS-NS offers a highly adaptable strategy for bioactive targeted nanotherapy for the delivery of FS and possibly other phytomedicines to treat breast cancer.

**Author Contributions:** Conceptualization, R.M.E.-M., A.H.E.-K. and A.A.A.; methodology, A.R.A., R.A.M., A.H.E.-K. and A.A.A.; software, A.R.A. and A.A.A.; validation, R.M.E.-M., A.H.E.-K. and A.A.A.; formal analysis, A.R.A., R.M.E.-M., R.A.M., B.A.B. and A.A.A.; investigation, A.R.A., R.A.M., A.H.E.-K. and B.A.B.; resources, A.R.A. and R.M.E.-M.; data curation, A.R.A., R.M.E.-M. and A.A.A.; writing original draft, A.R.A., R.M.E.-M., B.A.B. and A.A.A.; writing—review and editing, R.M.E.-M., A.H.E.-K., R.A.M., B.A.B. and A.A.A.; visualization, R.M.E.-M. and A.A.A.; supervision, R.M.E.-M., A.H.E.-K. and A.A.A.; project administration, A.H.E.-K.; funding acquisition, A.R.A. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** Animal studies were conducted according to the ethical guidelines and approved by the Institutional Ethics Committee of the Faculty of Pharmacy, Alexandria University, Alexandria, Egypt (protocol code AU-062023-1-141, and date of approval 24/1/2023). The MDA-MB-231 cell line was obtained from ATCC (HTB-26™) and cultured in CERRMA (Center of Excellence for Research in Regenerative Medicine and its Applications), Faculty of Medicine, Alexandria University.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** The data presented in this study are available in the article.

**Conflicts of Interest:** The authors declare no conflict of interest.

### **References**


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