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

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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.

Graphical abstract: Delivery of 5′-triphosphate RNA with endosomolytic nanoparticles potently activates RIG-I to improve cancer immunotherapy

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Publication details

The article was received on 01 Sep 2018, accepted on 13 Oct 2018 and first published on 24 Oct 2018


Article type: Paper
DOI: 10.1039/C8BM01064A
Citation: Biomater. Sci., 2019, Advance Article
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    Delivery of 5′-triphosphate RNA with endosomolytic nanoparticles potently activates RIG-I to improve cancer immunotherapy

    M. E. Jacobson, L. Wang-Bishop, K. W. Becker and J. T. Wilson, Biomater. Sci., 2019, Advance Article , DOI: 10.1039/C8BM01064A

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