Iron‐Deprivation Liposomes for Cancer Therapy

ABSTRACT Targeting iron homeostasis in tumor cells represents a promising anticancer strategy, as iron plays essential roles in tumor growth, invasion, and metastasis. Although deferoxamine can effectively chelate iron, its clinical application is limited by poor membrane permeability, short half‐life, and lack of targeting capability. To overcome these challenges, we designed and synthesized a family of DFO‐bearing lipids by modifying the molecule with dual fatty acid chains of varying lengths, and co‐assembled them with auxiliary lipids via microfluidics to construct “iron‐deprivation” liposomes. Among them, the medium‐chain DFO‐C12‐liposomes exhibited the highest cellular uptake, iron‐deprivation efficiency, and anticancer activity in vitro, markedly depleting mitochondrial iron, disrupting Fe–S cluster synthesis, suppressing mitochondrial respiration, and inducing autophagy. Furthermore, DFO‐C12‐liposomes efficiently coordinated Mn 2 + via DFO–Mn 2 + chelation, providing MRI capability while inducing iron deprivation–mediated ferroptosis. In addition, the iron‐deprivation liposomes can encapsulate anticancer drugs such as doxorubicin, leading to an enhanced antitumor effect through the combination of iron deprivation and chemotherapy for osteosarcoma treatment. In summary, the “iron‐deprivation” liposomes integrate iron chelation, imaging functionality, and chain‐length‐dependent cellular uptake into a versatile nanoplatform for regulating tumor iron homeostasis and achieving enhanced antitumor efficacy through multimodal therapeutic strategies.