Multiplex Methionine Modulating Hydrogel for Cancer Metabolic Therapy

Abstract The reliance on high levels of methionine by tumor cells provides an attractive target for cancer treatment. 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‐targeting nanoparticles (NPs) to achieve a cascaded blockage of intracellular methionine metabolism. These NPs are further co‐loaded with the extracellular methionine uptake inhibitor JPH203 into a type of reactive oxygen species‐sensitive hydrogel, assembling the multiplex methionine modulating hydrogel (3 M Gel). In murine models of triple‐negative breast cancer (TNBC), hepatocellular carcinoma, and colorectal cancer, the in situ formed 3 M Gel exhibits superior efficacy in restricting S‐adenosyl methionine generation and histone methylation, stimulating immunogenic cell death in tumor cells, thereby eliciting potent innate and adaptive immune responses to restrain tumor progression. Moreover, remodeling of the tumor microenvironment by 3 M Gel overcomes immune checkpoint blockade resistance in TNBC. This study presents a localized triple regulation strategy and paves a new path for amino acid starvation‐based cancer therapy.