Ligand-directed oral lipidic nanoplatform enables sustained ferroptosis and immune reprogramming via multivalent transporter-mediated metronomic delivery.

Rationale: Ferroptosis-induced tumor cell death and immune activation represent promising strategies for overcoming therapeutic resistance in triple-negative breast cancer (TNBC). However, clinical application remains limited by poor oral absorption, transient immune activation, and systemic toxicity. Methods: We developed an orally administrable nanoplatform (MCT-NE#9) co-delivering docetaxel (DTX) and atorvastatin (ATV), designed to enhance intestinal uptake via bile acid and vitamin transporters. Pharmacokinetic, in vitro, and in vivo studies were conducted to evaluate drug absorption, sustained ferroptosis, and immune modulation. Results: MCT-NE#9 markedly improved oral bioavailability (659% for ATV, 851% for DTX) and sustained intratumoral drug levels under a low-dose metronomic regimen. Mechanistically, it induced sustained ferroptosis by promoting iron accumulation, lipid peroxidation, and GPX4 suppression, while remodeling the tumor immune microenvironment. Treatment increased M1 macrophages and antigen-presenting cells and reduced TGFβ1, regulatory T cells, and M2 macrophages. In vivo, oral MCT-NE#9 suppressed tumor growth by 50.4%, with enhanced efficacy (70.3% inhibition) when combined with anti-CD47 therapy. Conclusion: MCT-NE#9 enables a synergistic, low-toxicity chemo-immunotherapeutic strategy by sustaining ferroptosis and reprogramming the immune microenvironment via transporter-targeted oral delivery. This ligand-directed nanoplatform offers a clinically translatable approach for effective TNBC treatment.