RESUMO
Inducing death receptor 5 (DR5) clustering holds particular promise in tumor-specific therapeutics because it could trigger an apoptotic cascade in cancerous cells. Herein, we present a tumor microenvironment H2O2-responsive self-illuminating nanoagonist, which could induce dual tumor cell death pathways through enhancing DR5 clustering. By conjugating DR5 ligand peptides onto the surfaces of self-illuminating nanoparticles with cross-linking capacity, this strategy not only provides scaffolds for ligands to bind receptors but also cross-links them through photo-cross-linking. This strategy allows for efficient activation of DR5 downstream signaling, initiating the extrinsic apoptosis pathway and immunogenic cell death of tumor cells, and contributes to improved tumor-specific immune responses, resulting in enhanced antitumor efficacy and minimized systemic adverse effects.
Assuntos
Nanopartículas , Receptores do Ligante Indutor de Apoptose Relacionado a TNF , Humanos , Animais , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/agonistas , Nanopartículas/química , Camundongos , Apoptose/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Morte Celular/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Neoplasias/metabolismo , Peróxido de Hidrogênio/química , Peróxido de Hidrogênio/metabolismo , Peptídeos/química , Peptídeos/farmacologiaRESUMO
Clustering of type II tumor necrosis factor (TNF) receptors (TNFRs) is essential for their activation, yet currently available drugs fail to activate signaling. Some strategies aim to cluster TNFR by using multivalent streptavidin or scaffolds based on dextran or graphene. However, these strategies do not allow for control of the valency or spatial organization of the ligands, and consequently control of the TNFR activation is not optimal. DNA origami nanostructures allow nanometer-precise control of the spatial organization of molecules and complexes, with defined spacing, number and valency. Here, we demonstrate the design and characterization of a DNA origami nanostructure that can be decorated with engineered single-chain TNF-related apoptosis-inducing ligand (SC-TRAIL) complexes, which show increased cell killing compared to SC-TRAIL alone on Jurkat cells. The information in this chapter can be used as a basis to decorate DNA origami nanostructures with various proteins, complexes, or other biomolecules.