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Fenton reaction centered ferroptosis-apoptosis synergetic therapy has emerged as a promising tumor elimination strategy. However, the low intracellular Fenton level and accumulation of therapeutics at the lesion site greatly limit the efficacy of ferroptosis therapy. To overcome these two bottlenecks, an inhalable metal polyphenol network (MPN)-hybrid liposome, encoded as LDG, was proposed for enhancing the intracellular Fenton reaction level by co-delivering the ferroptosis inducer dihydroartemisinin (DHA) and the ferrous ion (Fe2+) donor MPN. The synthesized LDG had excellent nebulization performance which significantly improved the accumulation in the lungs, about 8.2 times of intravenous injection. In terms of anticancer mechanisms, MPN raised the intracellular level of Fe2+ by constructing iron cycling in the weakly acidic environment of tumors. Triggered by Fe2+, DHA with peroxide-bridge structure underwent a high level of Fenton-like reaction, promoted the production of intracellular reactive oxygen species (ROS) and induced strong ferroptosis while cooperating with apoptosis. LDG exhibited extraordinary antitumor ability in an orthotopic lung tumor model, whose tumor inhibition efficiency was 1.53 (P = 0.0014) and 1.32 (P = 0.0183) times of the LG group (liposomes coated with gallic acid (GA)-Fe MPN) and LD group (liposomes loaded with DHA), respectively, showing the strongest anticancer effect. In conclusion, the constructed MPN-hybrid liposomes could be a potent custom nanoplatform for pulmonary delivery and underscored the great potential of ferroptosis-apoptosis synergetic therapy.
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