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However, systemic methionine blockade may raise concerns about potential side effects given the broad and essential functions of methionine in cellular metabolism. Here, a combined drug delivery platform for multilayered constraint of methionine within tumor lesions is developed. Small molecule inhibitors PF9366 and adenosine dialdehyde are encapsulated by tumor cell\u2010targeting nanoparticles (NPs) to achieve a cascaded blockage of intracellular methionine metabolism. These NPs are further co\u2010loaded with the extracellular methionine uptake inhibitor JPH203 into a type of reactive oxygen species\u2010sensitive hydrogel, assembling the multiplex methionine modulating hydrogel (3\u00a0M Gel). 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