Multilayer cascade-response nanoplatforms as metabolic symbiotic disruptors to reprogram the immunosuppressive...

Nanomedicine is extensively utilized in tumor treatment, however, the restricted permeability of nanomaterials within tumor tissues, along with the inherent metabolic complexity of these tissues, have hindered effective control of tumor progression. Hypoxic and normoxic tumor cells utilize monocarboxylic acid transporters (MCTs) for the rapid reutilization of lactate, facilitating accelerated tumor growth. Here, cascade-response nanoplatforms (NPs) with contrast-enhanced ultrasound imaging (CEUI) capability had been established, incorporating basigin siRNA internally and featuring hyaluronidase (HAase) and γ-glutamyltranspeptidase (GGT)-responsive lipid coatings externally (GHB NPs). The GHB NPs took advantage of GGT-responsive HAase release to facilitate deep tumor penetration. Furthermore, ultrasound (US) irradiation decreased the expression of glycolysis-related proteins through the modulation of the β-catenin/c-Myc pathway, and US irradiation induced mitochondrial damage, leading to a low-energy state in tumor cells. On this basis, GHB NPs was paired with US stimulation to provide a combination therapy that disturbed tumor cell metabolic symbiosis and remodeled the immunosuppressive tumor microenvironment. This study formulates an effective therapeutic approach for metabolic-immunotherapy, potentially offering a viable candidate for tumor treatment.