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

Abstract

Competitive consumption of nutrients between rapidly proliferating cancer cells and T cells results in an immunosuppressive tumor microenvironment (TME) and nutrient deprivation of T cells, which can cause low response rate and resistance to immunotherapies. In this study, we proposed a dual-mechanism based nutrient partitioning nanoregulator (designated as DMNPN), which can simultaneously regulate the immunosuppressive TME and enhance T cell nutrient availability. DMNPN consists of a charge-reversal biodegradable mesoporous silica, encapsulating glycolysis inhibitor lonidamine, and small interfering RNA against glutaminase. Through inhibiting glycolysis to decrease the lactic acid production and downregulating glutaminase expression to reduce the uptake of glutamine by tumor cells, DMNPN enables effective remodeling of metabolism and nutrient partitioning, which alleviates the immunosuppressive TME and boosts nutrient availability for T cells with enhanced antitumor immunity. Such a nutrient partitioning nanoregulator can effectively inhibit 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 provides a promising approach for cancer therapy.

Glutathione-sensitive mesoporous nanoparticles loaded with cinnamaldehyde for chemodynamic and immunological therapy of cancer

“…Accordingly, the spherical MONs with diameters of 55.9 ± 6.3 nm have been successfully synthesized with evident mesoporous structure. 49 The loaded CA was partially filled in the mesoporous structure of nanoparticles, resulting in a smoother surface. After coating with HA, a low contrast wrapping layer of approximately 77.9 ± 9.8 nm can be clearly observed, which effectively increases the particle size.…”

Amino Acid Metabolism-Regulated Nanomedicine for Enhanced Tumor Immunotherapy through Synergistic Regulation of Immune Microenvironment

“…Given this, inhibiting glycolysis to disrupt the energy supply of tumor cells is a widely studied approach for metabolic intervention. Recently, a variety of biomaterials have been developed to suppress glycolysis for tumor combinational immunotherapy, including metal-organic frameworks, nanomicelles, and mesoporous silica NPs [ 48 , 49 ]. Among them, stimuli-responsive nanomedicine, triggered by endogenous factors (such as low pH, overexpressed enzymes, high levels of redox agents, and ATP) and/or exogenous stimuli (such as light, radiation, ultrasound, and temperature), have garnered increased attention for tumor-specific treatments [ 50 ].…”

Tumor Metabolism-Rewriting Nanomedicines for Cancer Immunotherapy

“…Recently, a nutrient partitioning nanoregulator (DMNPN) with GSH responsiveness and pH-triggered charge reversal properties was developed to concurrently inhibit glycolysis and glutamine metabolism in cancer cells (Table 3). 125 DMNPN was prepared by loading glycolysis inhibitor LND into aminofunctionalized, disulfide-bonded mesoporous organosilica NPs (NH 2 -MONs). The surface of NH 2 -MONs was then coated with cationic PEI and poly(allylamine hydrochloride)citraconic anhydride (PAH-cit), which not only facilitated loading of antiglutaminase siRNA (siGLS) via electrostatic interaction but also prevented the premature release of LND.…”