Lactoferrin-modified niclosamide lipid nanocarriers reprogram ferroptosis and antioxidant networks for breast cancer suppression.

Repurposing niclosamide (Nic), an FDA-approved anthelmintic with emerging anticancer potential, offers a promising strategy for breast cancer therapy. However, its clinical translation is limited by poor solubility and bioavailability. In this study, Nic was encapsulated into bioactive Nigella sativa incorporated nanostructured lipid carriers (Nic-NLC) and further functionalized with lactoferrin (LF-Nic-NLC) to enhance the tumor-specific targeting and cellular uptake. The selected LF-Nic-NLC showed a particle size of 133.43 ± 0.8 nm and a zeta potential of -10.7 ± 0.3 mV with high entrapment efficiency exceeding 99 % and sustained drug release. In-vitro studies on MDA-MB-231 cells showed potent cytotoxic effect (IC 6.826 µg/mL), improved internalization (7.9-fold increase compared to coumarin 6), reduced migration (30.61 ± 4.51 % wound closure) and enhanced apoptotic effect. Moreover, LF-Nic-NLC demonstrated an efficient antitumor activity following both oral and intraperitoneal administration when tested in an Ehrlich ascites mammary tumor model. Results indicated strong tumor growth inhibition. The histopathological assessment using the Miller-Payne grading system revealed grade 4-5, indicating marked to near-complete tumor regression. At the molecular level, Nic-based therapies enhanced ferroptotic signaling, evidenced by increased transferrin receptor and ALOX15, along with suppression of DHODH, NRF2, and oncogenic miR-522, thereby promoting lipid peroxidation and ferroptotic vulnerability. Concurrently, VEGF downregulation and p53 upregulation reflected additional anti-angiogenic and pro-apoptotic effects. Collectively, the lactoferrin-functionalized Nic-NLC produced the most robust antitumor response, with superior ferroptosis induction, redox modulation, and anti-angiogenic activity.