Dysfunctional endothelium contributes to more diseases than any other tissue in the body. Small interfering RNAs (siRNAs) can help in the study and treatment of endothelial cells in vivo by durably silencing multiple genes simultaneously, but efficient siRNA delivery has so far remained challenging. Here, we show that polymeric nanoparticles made of low-molecular-weight polyamines and lipids can deliver siRNA to endothelial cells with high efficiency, thereby facilitating the simultaneous silencing of multiple endothelial genes in vivo. Unlike lipid or lipid-like nanoparticles, this formulation does not significantly reduce gene expression in hepatocytes or immune cells even at the dosage necessary for endothelial gene silencing. These nanoparticles mediate the most durable non-liver silencing reported so far and facilitate the delivery of siRNAs that modify endothelial function in mouse models of vascular permeability, emphysema, primary tumour growth and metastasis.
At a glance
- Evolving functions of endothelial cells in inflammation. Nature Rev. Immunol. 7, 803–815 (2007). &
- Targeting VEGF-B as a novel treatment for insulin resistance and type 2 diabetes. Nature 490, 426–430 (2012). et al.
- Robbins and Cotran Pathologic Basis of Disease 8th edn (Elsevier, 2009). , , &
- Delivery materials for siRNA therapeutics. Nature Mater. 12, 967–977 (2013). , , &
- Lipid-like materials for low-dose, in vivo gene silencing. Proc. Natl Acad. Sci. USA 107, 1864–1869 (2010). et al.
- Rational design of cationic lipids for siRNA delivery. Nature Biotechnol. 28, 172–176 (2010). et al.
- Knocking down barriers: advances in siRNA delivery. Nature Rev. Drug Discov. 8, 129–138 (2009). , &
- Atu027, a liposomal small interfering RNA formulation targeting protein kinase N3, inhibits cancer progression. Cancer Res. 68, 9788–9798 (2008). et al.
- Intracellular localization of lipoplexed siRNA in vascular endothelial cells of different mouse tissues. Microvasc. Res. 76, 31–41 (2008). et al.
- RNA interference in the mouse vascular endothelium by systemic administration of siRNA-lipoplexes for cancer therapy. Gene Ther. 13, 1360–1370 (2006). et al.
- A novel siRNA-lipoplex technology for RNA interference in the mouse vascular endothelium. Gene Ther. 13, 1222–1234 (2006). et al.
- Delivery of siRNA to the mouse lung via a functionalized lipopolyamine. Mol. Ther. 20, 91–100 (2012). et al.
- RNA interference for therapy in the vascular endothelium. Microvasc. Res. 80, 286–293 (2010). , &
- Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles. Nature 484, 1067–1070 (2010). et al.
- Dynamic polyconjugates for targeted in vivo delivery of siRNA to hepatocytes. Proc. Natl Acad. Sci. USA 104, 12982–12987 (2007). et al.
- Poly(ethylenimine) and its role in gene delivery. J. Control. Rel. 60, 149–160 (1999). , &
- Breaking up the correlation between efficacy and toxicity for nonviral gene delivery. Proc. Natl Acad. Sci. USA 104, 14454–14459 (2007). , , &
- Biophysical and structural characterization of polyethylenimine-mediated siRNA delivery in vitro. Pharm. Res. 8, 1868–1876 (2006). , &
- Analysis of lipid nanoparticles by cryo-EM for characterizing siRNA delivery vehicles. Int. J. Pharm. 403, 237–244 (2011). et al.
- Maximizing the potency of siRNA lipid nanoparticles for hepatic gene silencing in vivo. Angew. Chem. Int. Ed. 51, 8529–8533 (2012). et al.
- Targeting the ANGPT-TIE2 pathway in malignancy. Nature Rev. Cancer 10, 575–585 (2010). , , &
- Systemic RNAi-mediated gene silencing in nonhuman primate and rodent myeloid cells. Mol. Ther. Nucleic Acids 1, e4 (2012). et al.
- Inhibition of VEGF receptors causes lung cell apoptosis and emphysema. J. Clin. Invest. 106, 1311–1319 (2000). et al.
- Vascular endothelial growth factor of the lung: friend or foe. Curr. Opin. Pharmacol. 8, 255–260 (2008). &
- The Delta paradox: DLL4 blockade leads to more tumour vessels but less tumour growth. Nature Rev. Cancer 7, 327–331 (2007). , &
- FLT1 and its ligands VEGFB and PlGF: drug targets for anti-angiogenic therapy? Nature Rev. Cancer 8, 942–956 (2008). , , &
- Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nature Med. 7, 1194–1201 (2001). et al.
- VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438, 820–827 (2005). et al.
- VEGFR-3 controls tip to stalk conversion at vessel fusion sites by reinforcing Notch signalling. Nature Cell Biol. 13, 1202–1213 (2011). et al.
- Heterogeneity of cell death. Cytogenet. Genome Res. 139, 164–173 (2013). et al.
- Dll4-Fc, an inhibitor of Dll4-notch signaling, suppresses liver metastasis of small cell lung cancer cells through the downregulation of the NF-kappaB activity. Mol. Cancer Ther. 11, 2578–2587 (2012). et al.
- Notch: a key regulator of tumor angiogenesis and metastasis. Histol. Histopathol. 27, 151–156 (2012). &
- Targeted delivery of RNAi therapeutics with endogenous and exogenous ligand-based mechanisms. Mol. Ther. 18, 1357–1364 (2010). et al.
- Biomolecular coronas provide the biological identity of nanosized materials. Nature Nanotech. 7, 779–786 (2012). , , &
- Rapid discovery of potent siRNA-containing lipid nanoparticles enabled by controlled microfluidic formulation. J. Am. Chem. Soc. 134, 6948–6951 (2012). et al.
- Silencing or stimulation? siRNA delivery and the immune system. Ann. Rev. Chem. Biomol. Eng. 2, 77–96 (2011). , , &
- Epoxyeicosanoids stimulate multiorgan metastasis and tumor dormancy escape in mice. J. Clin. Invest. 122, 178–191 (2012). et al.
- Supplementary information (2,130 KB)