Hijacking cysteine metabolism for reversing hydrogen sulfide production in enhanced ferroptosis therapy

Intracellular cysteine (Cys) is an essential element in glutathione (GSH) biosynthesis, which endows cancer cell resistance to various therapies. In this study, we design a Cys metabolism hijacking strategy for converting cytoprotective Cys into therapeutic hydrogen sulfide (H2S), thus achieving enhanced ferroptosis therapy. A therapeutic nanoagent is first synthesized via the co-assembly of L-buthionine-sulfoximine (BSO) and plasmid encoding fn1055 with metal–organic framework (MOF) Fenton catalyst. The encapsulated BSO blocks the Cys-GSH biosynthesis pathway while the Fn1055 protein expressed from plasmid catalyzes the conversion of intracellular Cys to H2S, accelerating Cys-H2S metabolism. Due to its triple functionalities of intracellular acidification, catalase inhibition and mitophagy promotion, H2S significantly accelerates the MOF-induced ferroptosis, which is rationalized by the fully shrunken mitochondria. The in vivo administration of nanoagent effectively suppresses xenograft tumor growth without appreciable side effect. Such Cys metabolism hijacking provides a proof of concept for remolding the Cys-GSH pathway as a promising therapeutic strategy in cancer therapy.