A Dual-Mechanism Based Nutrient Partitioning Nanoregulator for Enhanced Immunotherapy against Anti-PD-1 Resistant Tumors

Competitive consumption of nutrients between rapidlyproliferatingcancer cells and T cells results in an immunosuppressive tumor microenvironment(TME) and nutrient deprivation of T cells, which can cause low responserate and resistance to immunotherapies. In this study, we proposeda dual-mechanism based nutrient partitioning nanoregulator (designatedas DMNPN), which can simultaneously regulate the immunosuppressiveTME and enhance T cell nutrient availability. DMNPN consists of acharge-reversal biodegradable mesoporous silica, encapsulating glycolysisinhibitor lonidamine, and small interfering RNA against glutaminase.Through inhibiting glycolysis to decrease the lactic acid productionand downregulating glutaminase expression to reduce the uptake ofglutamine by tumor cells, DMNPN enables effective remodeling of metabolismand nutrient partitioning, which alleviates the immunosuppressiveTME and boosts nutrient availability for T cells with enhanced antitumorimmunity. Such a nutrient partitioning nanoregulator can effectivelyinhibit the growth of anti-programmed death receptor 1 (anti-PD-1)resistant tumors and prevent tumor metastasis and recurrence. Overall,this dual-mechanism based nutrient reallocation strategy providesa promising approach for cancer therapy.