Dataset Information

Combined Chemisorption and Complexation Generate siRNA Nanocarriers with Biophysics Optimized for Efficient Gene Knockdown and Air-Blood Barrier Crossing.

ABSTRACT: Current nucleic acid (NA) nanotherapeutic approaches face challenges because of shortcomings such as limited control on loading efficiency, complex formulation procedure involving purification steps, low load of NA cargo per nanoparticle, endosomal trapping, and hampered release inside the cell. When combined, these factors significantly limit the amount of biologically active NA delivered per cell in vitro, delivered dosages in vivo for a prolonged biological effect, and the upscalability potential, thereby warranting early consideration in the design and developmental phase. Here, we report a versatile nanotherapeutic platform, termed auropolyplexes, for improved and efficient delivery of small interfering RNA (siRNA). Semitelechelic, thiolated linear polyethylenimine (PEI) was chemisorbed onto gold nanoparticles to endow them with positive charge. A simple two-step complexation method offers tunable loading of siRNA at concentrations relevant for in vivo studies and the flexibility for inclusion of multiple functionalities without any purification steps. SiRNA was electrostatically complexed with these cationic gold nanoparticles and further condensed with polycation or polyethyleneglycol-polycation conjugates. The resulting auropolyplexes ensured complete complexation of siRNA into nanoparticles with a high load of ?15,500 siRNA molecules/nanoparticle. After efficient internalization into the tumor cell, an 80% knockdown of the luciferase reporter gene was achieved. Auropolyplexes were applied intratracheally in Balb/c mice for pulmonary delivery, and their biodistribution were studied spatio-temporally and quantitatively by optical tomography. Auropolyplexes were well tolerated with ?25% of the siRNA dose remaining in the lungs after 24 h. Importantly, siRNA was released from auropolyplexes in vivo and a fraction also crossed the air-blood barrier, which was then excreted via kidneys, whereas >97% of gold nanoparticles were retained in the lung. Linear PEI-based auropolyplexes offer a combination of successful endosomal escape and better biocompatibility profile in vivo. Taken together, combined chemisorption and complexation endow auropolyplexes with crucial biophysical attributes, enabling a versatile and upscalable nanogold-based platform for siRNA delivery in vitro and in vivo.

SUBMITTER: Taschauer A

PROVIDER: S-EPMC7467563 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Combined Chemisorption and Complexation Generate siRNA Nanocarriers with Biophysics Optimized for Efficient Gene Knockdown and Air-Blood Barrier Crossing.

Taschauer Alexander A Polzer Wolfram W Pöschl Stefan S Metz Slavica S Tepe Nathalie N Decker Simon S Cyran Norbert N Scholda Julia J Maier Julia J Bloß Hermann H Anton Martina M Hofmann Thilo T Ogris Manfred M Sami Haider H

ACS applied materials & interfaces 20200623 27

Current nucleic acid (NA) nanotherapeutic approaches face challenges because of shortcomings such as limited control on loading efficiency, complex formulation procedure involving purification steps, low load of NA cargo per nanoparticle, endosomal trapping, and hampered release inside the cell. When combined, these factors significantly limit the amount of biologically active NA delivered per cell <i>in vitro</i>, delivered dosages <i>in vivo</i> for a prolonged biological effect, and the upsca ...[more]

PMID: 32515194

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Project description:Accurate barriers for rate controlling elementary reactions on metal surfaces are key to understanding, controlling, and predicting the rate of heterogeneously catalyzed processes. While barrier heights for gas phase reactions have been extensively benchmarked, dissociative chemisorption barriers for the reactions of molecules on metal surfaces have received much less attention. The first database called SBH10 and containing 10 entries was recently constructed based on the specific reaction parameter approach to density functional theory (SRP-DFT) and experimental results. We have now constructed a new and improved database (SBH17) containing 17 entries based on SRP-DFT and experiments. For this new SBH17 benchmark study, we have tested three algorithms (high, medium, and light) for calculating barrier heights for dissociative chemisorption on metals, which we have named for the amount of computational effort involved in their use. We test the performance of 14 density functionals at the GGA, GGA+vdW-DF, and meta-GGA rungs. Our results show that, in contrast with the previous SBH10 study where the BEEF-vdW-DF2 functional seemed to be most accurate, the workhorse functional PBE and the MS2 density functional are the most accurate of the GGA and meta-GGA functionals tested. Of the GGA+vdW functionals tested, the SRP32-vdW-DF1 functional is the most accurate. Additionally, we found that the medium algorithm is accurate enough for assessing the performance of the density functionals tested, while it avoids geometry optimizations of minimum barrier geometries for each density functional tested. The medium algorithm does require metal lattice constants and interlayer distances that are optimized separately for each functional. While these are avoided in the light algorithm, this algorithm is found not to give a reliable description of functional performance. The combination of relative ease of use and demonstrated reliability of the medium algorithm will likely pave the way for incorporation of the SBH17 database in larger databases used for testing new density functionals and electronic structure methods.

Dataset Information

Combined Chemisorption and Complexation Generate siRNA Nanocarriers with Biophysics Optimized for Efficient Gene Knockdown and Air-Blood Barrier Crossing.

Publications

Combined Chemisorption and Complexation Generate siRNA Nanocarriers with Biophysics Optimized for Efficient Gene Knockdown and Air-Blood Barrier Crossing.

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