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Biomater Sci. 2019 Jan 29;7(2):547-559. doi: 10.1039/c8bm01064a.

Delivery of 5'-triphosphate RNA with endosomolytic nanoparticles potently activates RIG-I to improve cancer immunotherapy.

Author information

1
Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN 37235, USA. john.t.wilson@vanderbilt.edu.

Abstract

RNA agonists of the retinoic acid gene I (RIG-I) pathway have recently emerged as a promising class of cancer immunotherapeutics, but their efficacy is hindered by drug delivery barriers, including nuclease degradation, poor intracellular uptake, and minimal access to the cytosol where RIG-I is localized. Here, we explore the application of pH-responsive, endosomolytic polymer nanoparticles (NPs) to enhance the cytosolic delivery and immunostimulatory activity of synthetic 5' triphosphate, short, double-stranded RNA (3pRNA), a ligand for RIG-I. Delivery of 3pRNA with pH-responsive NPs with an active endosomal escape mechanism, but not control carriers lacking endosomolytic activity, significantly increased the activity of 3pRNA in dendritic cells, macrophages, and cancer cell lines. In a CT26 colon cancer model, activation of RIG-I via NP delivery of 3pRNA induced immunogenic cell death, triggered expression of type I interferon and pro-inflammatory cytokines, and increased CD8+ T cell infiltration into the tumor microenvironment. Consequently, intratumoral (IT) delivery of NPs loaded with 3pRNA inhibited CT26 tumor growth and enhanced the therapeutic efficacy of anti-PD-1 immune checkpoint blockade, resulting in a 30% complete response rate and generation of immunological memory that protected against tumor rechallenge. Collectively, these studies demonstrate that pH-responsive NPs can be harnessed to strongly enhance the immunostimulatory activity and therapeutic efficacy of 3pRNA and establish endosomal escape as a critical parameter in the design of carriers for immunotherapeutic targeting of the RIG-I pathway.

PMID:
30379158
DOI:
10.1039/c8bm01064a
[Indexed for MEDLINE]

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