Highlights
aCD3/F/AN, anti-CD3e f(ab′)2 fragment-modified and fenofibrate-encapsulated amphiphilic nanoparticle, reprogrammed mitochondrial lipid metabolism of T cells.
aCD3/F/AN specifically activated T cells in glucose-deficient conditions mimicking tumor microenvironment, and exerted an effector killing effect against tumor cells.
In vivo treatment with aCD3/F/AN increased T cell infiltration, cytokine production, and prevented tumor growth.
Abstract
We report the activation of anticancer effector functions of T cells through nanoparticle-induced lipid metabolic reprogramming. Fenofibrate was encapsulated in amphiphilic polygamma glutamic acid-based nanoparticles (F/ANs), and the surfaces of F/ANs were modified with an anti-CD3e f(ab′)2 fragment, yielding aCD3/F/ANs. An in vitro study reveals enhanced delivery of aCD3/F/ANs to T cells compared with plain F/ANs. aCD3/F/AN-treated T cells exhibited clear mitochondrial cristae, a higher membrane potential, and a greater mitochondrial oxygen consumption rate under glucose-deficient conditions compared with T cells treated with other nanoparticle preparations. Peroxisome proliferator-activated receptor-α and downstream fatty acid metabolism-related genes are expressed to a greater extent in aCD3/F/AN-treated T cells. Activation of fatty acid metabolism by aCD3/F/ANs supports the proliferation of T cells in a glucose-deficient environment mimicking the tumor microenvironment. Real-time video recordings show that aCD3/F/AN-treated T cells exerted an effector killing effect against B16F10 melanoma cells. In vivo administration of aCD3/F/ANs can increase infiltration of T cells into tumor tissues. The treatment of tumor-bearing mice with aCD3/F/ANs enhances production of various cytokines in tumor tissues and prevented tumor growth. Our findings suggest the potential of nanotechnology-enabled reprogramming of lipid metabolism in T cells as a new modality of immunometabolic therapy.
Genome-editing technology has emerged as a potential tool for treating incurable diseases for which few therapeutic modalities are available. In particular, discovery of the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas system together with the design of single-guide RNAs (sgRNAs) has sparked medical applications of genome editing. Despite the great promise of the CRISPR/Cas system, its clinical application is limited, in large part, by the lack of adequate delivery technology. To overcome this limitation, researchers have investigated various systems, including viral and nonviral vectors, for delivery of CRISPR/Cas and sgRNA into cells. Among nonviral delivery systems that have been studied are nanovesicles based on lipids, polymers, peptides, and extracellular vesicles. These nanovesicles have been designed to increase the delivery of CRISPR/Cas and sgRNA through endosome escape or using various stimuli such as light, pH, and environmental features. This review covers the latest research trends in nonviral, nanovesicle-based delivery systems that are being applied to genome-editing technology and suggests directions for future progress.
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