Reductively Responsive Hydrogel Nanoparticles with Uniform Size, Shape, and Tunable Composition for Systemic siRNA Delivery in Vivo.
To achieve the great potential of siRNA based gene therapy, safe and efficient systemic delivery in vivo is essential. Here we report reductively responsive hydrogel nanoparticles with highly uniform size and shape for systemic siRNA delivery in vivo. "Blank" hydrogel nanoparticles with high aspect ratio were prepared using continuous particle fabrication based on PRINT (particle replication in nonwetting templates). Subsequently, siRNA was conjugated to "blank" nanoparticles via a disulfide linker with a high loading ratio of up to 18 wt %, followed by surface modification to enhance transfection. This fabrication process could be easily scaled up to prepare large quantity of hydrogel nanoparticles. By controlling hydrogel composition, surface modification, and siRNA loading ratio, siRNA conjugated nanoparticles were highly tunable to achieve high transfection efficiency in vitro. FVII-siRNA conjugated nanoparticles were further stabilized with surface coating for in vivo siRNA delivery to liver hepatocytes, and successful gene silencing was demonstrated at both mRNA and protein levels.
Department of Chemistry, University of North Carolina, Chapel Hill, North Carolina 27599, United States.|Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599, United States.
Da
D
Ma
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599, United States.|Carolina Center of Cancer Nanotechnology Excellence, University of North Carolina, Chapel Hill, North Carolina 27599, United States.|Department of Microbiology & Immunology, University of North Carolina, Chapel Hill, North Carolina 27599, United States.
Shaomin
S
Tian
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States.
Jeremy
J
Baryza
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599, United States.|Carolina Center of Cancer Nanotechnology Excellence, University of North Carolina, Chapel Hill, North Carolina 27599, United States.|Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, United States.
J Christopher
JC
Luft
Department of Chemistry, University of North Carolina, Chapel Hill, North Carolina 27599, United States.|Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599, United States.|Carolina Center of Cancer Nanotechnology Excellence, University of North Carolina, Chapel Hill, North Carolina 27599, United States.|Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina 27599, United States.|Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, United States.|Institute for Advanced Materials, University of North Carolina, Chapel Hill, North Carolina 27599, United States.|Institute for Nanomedicine, University of North Carolina, Chapel Hill, North Carolina 27599, United States.|Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, North Carolina 27695, United States.|Sloan-Kettering Institute for Cancer Research, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, United States.
Joseph M
JM
DeSimone
D000818:Animals; D016503:Drug Delivery Systems / Q000379:methods; D004587:Electrophoresis, Agar Gel; D006367:HeLa Cells; D006801:Humans; D020100:Hydrogels / Q000627:therapeutic use*; D008810:Mice, Inbred C57BL; D008855:Microscopy, Electron, Scanning; D053758:Nanoparticles / Q000737:chemistry / Q000627:therapeutic use*; D010316:Particle Size; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000627:therapeutic use
D020100:Hydrogels; D034741:RNA, Small Interfering
drug delivery; gene therapy; hydrogel; nanoparticles; siRNA