Endowed with porous architectures, metal-organic framework (MOF) offers exceptional potentials for enhancing loading capacities of therapeutic drugs and facilitating biocatalysis in vivo. In this study, a type of hybrid nanosheet (L-Arg/ICG@MOF-5-CORM-FA, LIMF) was constructed, and gas prodrugs of L-arginine (L-Arg) and carbonyl manganese-401 (CORM) were co-encapsulated, while its surface-gated folic acid-polyethylene glycol-thiol structure effectively prevented leakage of payloads. Acidic tumor environment paved the way to sustained release of carbon oxide (CO) and manganese ions from CORM, while the production of reactive oxygen species further oxidized L-Arg to produce nitride oxide (NO). Upon intravenous injection, LIMF nanosheets actively targeted the tumor site and exerted combinational therapeutic effects, including ultrasound-mediated piezoelectric dynamic effect, Fenton-like reaction as well as the release of CO/NO gases in situ. Notably, sustainable productions of oxidative stress and CO/NO were accompanied by downregulated glutathione peroxidase and excessive intracellular lipid peroxide accumulation, which synergistically led to a tumor ablation rate of 89.3% in vivo. Therefore, these engineered hybrid nanosheet suggested a promising and versatile platform to integrate gas therapy and ferroptosis, ultimately enabling synergistic suppression of tumor cell proliferation and progression.
Lin et al. (Fri,) studied this question.