Fe2O3 Hollow Multishelled Structure Endowed Temporal Sequential Mass Release for Apoptosis/Ferroptosis‐Induced Combined Cancer Therapy

Abstract Cisplatin (CDDP) combined with pemetrexed (MTA) is commonly employed in the treatment of advanced non‐small cell lung cancer. However, conventional clinical administration methods fail to achieve precise spatiotemporal delivery within the tumor microenvironment (TME), resulting in inadequate control of local drug concentrations and impeding the synergistic efficacy of chemotherapeutic drugs. Aiming to address this issue, Fe 2 O 3 hollow multi‐shelled structure (HoMS) nanocarriers with spatiotemporally controlled release properties and co‐encapsulated CDDP and MTA into this nanocarrier are developed. The confined microenvironment provided by Fe 2 O 3 ‐HoMS enables a targeted and temporal sequential drug release tailored to clinical requirements. Furthermore, chemotherapy‐induced DNA damage leads to apoptosis, accompanied by a substantial generation of reactive oxygen species (ROS). The disruption of ROS homeostasis subsequently activates the ferroptosis pathway mediated by Fe 2 O 3 ‐HoMS. In summary, Fe 2 O 3 ‐HoMS exhibits a highly controlled and temporal sequential release of two chemotherapeutic drugs in TME, and the HoMS nanocarriers are further involved in the regulation of ferroptosis, realizing a triple sequential delivery system comprising CDDP‐MTA‐Fe 2+ and thus significantly enhancing the anti‐tumor efficacy against lung cancer. This study proposes a novel approach for temporal sequential drug delivery by optimizing nanocarrier design, addressing the clinical challenge of precisely controlled drug release within tumors.