Harnessing Nature for Breast Cancer Management: Effects of Fisetin-Loaded Nigellasomes Embedded in Microneedles Improve Tumor Suppression and Reduce Oxidative Stress

<b>Background</b>: Natural compounds such as fisetin have promising in breast cancer treatment, but their poor pharmacokinetics limit their therapeutic application. This study utilized a synergistic approach by combining fisetin-loaded <i>Nigella sativa</i> (N.S.) oil nanovesicles (FIS-NSs) and carbohydrate-based microneedles (FIS-NSs-MNs) to improve breast cancer management. <b>Methods</b>: Chemical composition of NS petroleum ether extract using gas chromatography-mass spectrometry (GC/MS). FIS-NSs were prepared and characterized for particle size, polydispersity, zeta potential, encapsulation efficiency, and stability. These vesicles were embedded into gelatin, hyaluronic acid, and carboxymethyl cellulose microneedles. In vitro drug release, ex vivo permeation, cytotoxicity against breast cancer cells, and in vivo antitumor efficacy in Ehrlich tumor models were evaluated. <b>Results</b>: Optimized FIS-NSs displayed nanoscale size (190 ± 0.74 nm), low P.D.I (0.25 ± 0.07), high surface charge (+37 ± 0.57 mV), and high encapsulation (88 ± 0.77%). In vitro investigations showed sustained FIS release (~85% over 72 h), while ex vivo permeation showed higher absorption than free fisetin. Both FIS-NSs and FIS-NSs-MNs showed dose-dependent cytotoxicity against breast cancer cells, with lower IC₅₀ than free fisetin (24.7 µM). In vivo, FIS-NSs-MNs and tumor burden inhibition (~77%), reduced oxidative stress (54%), restored antioxidant defenses, and decreased inflammatory markers. Immunohistochemical analysis for caspase-3 showed apoptosis activation within tumor tissues. <b>Conclusions</b>: These findings demonstrate that FIS administration via NS-MNs improves drug stability, penetration, and apoptotic activity, resulting in enhanced anticancer effects. This innovative nanovesicle-microneedle platform provides a non-invasive, effective, and patient-friendly approach for the effective treatment of breast cancer, with potential for broader applications in oncological nanomedicine.