Selective Methionine Pool Exhaustion Mediated by a Sequential Positioned MOF Nanotransformer for Intense Cancer Immunotherapy.

Abstract

Cancer cells are addictive to exogenous methionine to gear toward tumor proliferation. Meanwhile, they could replenish methionine pool from polyamine metabolism through methionine salvage pathway. However, the current developed therapeutic tactics for methionine depletion remain facing great challenges in terms of the selectivity, safety and efficiency. Herein, a sequential positioned metal organic framework (MOF) nanotransformer was designed to selectively exhaust methionine pool via inhibiting the uptake of methionine and throttling its salvage pathway for enhanced cancer immunotherapy. The MOF nanotransformer could restrain the open source and reduce the reflux of methionine to exhaust methionine pool of cancer cells. Moreover, the intracellular traffic routes of sequential positioned MOF nanotransformer matched well with the distribution of polyamines, which was conducive to the oxidation of polyamines via its responsive deformability and nanozyme-augmented Fenton-like reaction for the final exhaustion of intracellular methionine. Our results verified that the well-designed platform could not only kill cancer cells efficiently but also promote the infiltration of CD8 and CD4 T cells for intensive cancer immunotherapy. Overall, we believe that our work will inspire the construction of novel MOF-based antineoplastic platform and provide new insights into the development of metabolic-related immunotherapy. This article is protected by copyright. All rights reserved.