Targeted Nanoparticle Delivery of Bifunctional RIG-I Agonists to Pancreatic Cancer

• Published in: Molecular therapy 2019-03, Vol.27 (3), p.491-492
• Main Authors: Zillinger, Thomas, Hartmann, Gunther
• Format: Article
• Language: English
• Subjects: Acids; Adenocarcinoma; Apoptosis; Bcl-2 protein; Cancer therapies; Cytosol; Double-stranded RNA; Humans; Immune system; Immunogenicity; Immunotherapy; Inflammation; Interferon; Ligands; Mitochondria; Nanoparticles; p53 Protein; Pancreatic cancer; Pancreatic Neoplasms; Proteins; Retinoic acid; Sigma receptors; siRNA; Tumors
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1016/j.ymthe.2019.02.005

Main Text In this issue of Molecular Therapy, Das et al.1 harness surface-receptor targeting nanoparticle delivery to combat pancreatic ductal adenocarcinoma with bifunctional short interfering RNA (siRNA), which activates the innate immune receptor retinoic acid-inducible gene I (RIG-I) and silences the anti-apoptotic protein Bcl-2. RIG-I detects 5′-tri- or diphosphorylated double-stranded RNA, which is generated in the cytosol during viral infection,3–5 and signals via the adaptor protein MAVS (mitochondrial antiviral-signaling protein), leading to the production of type I interferon and pro-inflammatory cytokines.6 Stimulating this response with agonistic RNAs can be exploited to direct the adaptive immune system against cancer cells and generate an immunogenic tumor microenvironment.7 In addition, RIG-I activation can induce expression of the pro-apoptotic Bcl-2 family members Puma (p53 upregulated modulator of apoptosis) and Noxa, which leads to efficient induction of apoptosis in many tumors, but not in primary cells.8 Antagonizing anti-apoptotic Bcl-2 can further enhance tumor cell-specific apoptosis. Sigma receptors are highly expressed on many tumors12 and, although their natural ligands and function are incompletely understood, the Sigma1-receptor ligand anisamide is frequently used as a nanoparticle surface modification to enable tumor targeting in vivo.13 In an orthotopic allograft mouse model of PDAC, Das et al.1 show that two low doses (5 μg per mouse and injection) of nanoparticles encapsulating a RIG-I-activating Bcl-2 siRNA are sufficient to induce tumor regression.