A sequentially programmed Fe2O3 hollow multishelled nanoplatform for ferroptosis-amplified lung cancer therapy and macrophage-related innate immune remodeling

Lung cancer chemotherapy is often limited by insufficient tumor-selective drug delivery, premature leakage, and the difficulty of coordinating multiple therapeutic mechanisms in an optimal temporal sequence. Here, we developed a sequentially programmed Fe 2 O 3 hollow multishelled nanoplatform, Fe 2 O 3 -HoMS-(SS-ART)-Oxa@CaP, to achieve shell-selective loading and microenvironment-responsive release for chemo-ferroptotic therapy. In this design, oxaliplatin (Oxa) was preferentially positioned in the outer shell/pore region for relatively early release, whereas a reduction-responsive disulfide-linked artesunate prodrug (SS-ART) was confined within the inner structure for delayed glutathione-triggered activation, and an ultrathin CaP layer served as an acid-responsive gatekeeper. This structural organization enabled a programmed release tendency that supports early chemotherapeutic priming followed by redox amplification. Mechanistically, Fe 2 O 3 -HoMS-(SS-ART)-Oxa@CaP increased intracellular Fe 2+ availability and ROS accumulation, depleted GSH, and suppressed GPX4, with results consistent with enhanced ferroptosis-related tumor cell damage. The nanoformulation also induced CRT exposure and HMGB1 redistribution, suggesting immunogenic cell death-associated molecular changes. Functionally, it significantly inhibited A549 cell proliferation, migration, and invasion compared with free drugs and their free combination. In vivo, the nanoplatform achieved improved tumor suppression, increased TUNEL positivity, reduced GPX4 expression, prolonged survival, and was associated with a shift in tumor-associated macrophages toward a more CD86-positive/M1-like and less CD206-positive/M2-like phenotype, with no obvious systemic toxicity under the tested conditions. Together, these findings support this Fe 2 O 3 -based hollow multishelled nanoplatform as a proof-of-concept strategy for programmed chemo-ferroptotic therapy in lung cancer, while also suggesting macrophage-related innate immune changes in vivo.