Abstract:
:Two of the most prominent challenges that limit the clinical success of siRNA therapies are a lack of control over cargo release from the delivery vehicle and an incomplete understanding of the link between gene silencing dynamics and siRNA dosing. Herein, we address these challenges through the formulation of siRNA polyplexes containing light-responsive polymer mixtures, whose varied compositions and triggered release behavior provide enhanced gene silencing and controlled dose responses that can be predicted by simple kinetic models. Through the straightforward mixing of two block copolymers, the level of gene knockdown was easily optimized to achieve the maximum level of GAPDH protein silencing in NIH/3T3 cells (~70%) using a single siRNA dose. The kinetic model was used to describe the dynamic changes in mRNA and protein concentrations in response to siRNA treatment. These predictions enabled the application of a second dose of siRNA to maximally suppress gene expression over multiple days, leading to a further 50% reduction in protein levels relative to those measured following a single dose. Furthermore, polyplexes remained dormant in cells until exposed to the photo-stimulus, demonstrating the complete control over siRNA activity as well as the stability of the nanocarriers. Thus, this work demonstrates that pairing advances in biomaterials design with simple kinetic modeling provides new insight into gene silencing dynamics and presents a powerful strategy to control gene expression through siRNA delivery. STATEMENT OF SIGNIFICANCE:Our manuscript describes two noteworthy impacts: (1) we designed mixed polymer formulations to enhance gene silencing, and (2) we simultaneously developed a simple kinetic model for determining optimal siRNA dose responses to maintain silencing over several days. These advances address critical challenges in siRNA delivery and provide new opportunities in therapeutics development. The structure-function relationships prevalent in these formulations were established to enable tuning and forecasting of nanocarrier efficiency a priori, leading to siRNA dosing regimens able to maximally suppress gene expression. Our advances are significant because the mixed polymer formulations provide a straightforward and scalable approach to tailor siRNA delivery regimens. Moreover, the implementation of accurate dosing frameworks addresses a major knowledge gap that has hindered clinical implementation of siRNA.
journal_name
Acta Biomaterjournal_title
Acta biomaterialiaauthors
Greco CT,Muir VG,Epps TH 3rd,Sullivan MOdoi
10.1016/j.actbio.2017.01.003subject
Has Abstractpub_date
2017-03-01 00:00:00pages
407-416eissn
1742-7061issn
1878-7568pii
S1742-7061(17)30003-Xjournal_volume
50pub_type
杂志文章abstract::Aortic aneurysm is a leading cause of death in adults, often taking lives without any premonitory signs or symptoms. Adverse clinical outcomes of aortic aneurysm are preventable by elective surgical repair; however, identifying at-risk individuals is difficult. The objective of this study was to perform a predictive b...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2013.07.044
更新日期:2013-12-01 00:00:00
abstract::Substrate stiffness is emerging as an effective tool for the regulation of cell behaviours such as locomotion, proliferation and differentiation. In order to explore the potential application of this biophysical tool, material platforms displaying lateral and continuously graded stiffness are advantageous since they a...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2011.09.030
更新日期:2012-02-01 00:00:00
abstract:UNLABELLED:Fluorescence microscopy and spectroscopy techniques are commonly used to investigate complex and interacting biological systems (e.g. proteins and nanoparticles in living cells), since these techniques can explore intracellular dynamics with high time resolution at the nanoscale. Here we extended one of the ...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2016.07.031
更新日期:2016-09-15 00:00:00
abstract::Biomaterial-mediated controlled release of soluble signaling molecules is a tissue engineering approach to spatially control processes of inflammation, microvascular remodeling and host cell recruitment, and to generate biochemical gradients in vivo. Lipid mediators, such as sphingosine 1-phosphate (S1P), are recogniz...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2014.08.007
更新日期:2014-11-01 00:00:00
abstract::Hyperthermia and local drug delivery have been proposed as potential therapeutic approaches for bone defects resulting from malignant bone tumors. The development of bioactive materials with magnetic and drug delivery properties may potentially meet this target. The aim of this study was to develop a multifunctional m...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2011.06.028
更新日期:2011-10-01 00:00:00
abstract::The fibrils in the bone matrix are glued together by extracellular matrix proteins to form laminated structures (osteons) to provide elasticity and a supportive substrate for osteogenesis. The objective of this work was to investigate material properties and osteogenic differentiation of bone marrow stromal (BMS) cell...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2009.12.003
更新日期:2010-06-01 00:00:00
abstract::A three-dimensional (3-D) cell culture system that allows control of both substrate stiffness and integrin binding density was created and characterized. This system consisted of two self-assembling peptide (SAP) sequences that were mixed in different ratios to achieve the desired gel stiffness and adhesiveness. The s...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2013.04.002
更新日期:2013-08-01 00:00:00
abstract::Two enzymes, thrombin and transglutaminase, both participate in the formation of fibrin networks and contribute to the mechanical strength of biogels. A theoretical model built from the available kinetic data showed that a competition may take place between the two enzymes for their common substrate, fibrinogen. To ev...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2009.08.001
更新日期:2010-02-01 00:00:00
abstract::Poly(ether ether ketone) (PEEK) and its composites are recognized as alternative bearing materials for use in arthroplasty because of their mechanical properties. The objective of this project was to evaluate the biological response of two different kinds of carbon fiber-reinforced (CFR) PEEK compared with ultra-high ...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2010.06.002
更新日期:2010-11-01 00:00:00
abstract::First-principles calculations were carried out to reveal local atomic arrangements and thermodynamic stability of substitutional divalent cations of Mg(2+), Zn(2+), Sr(2+) and Ba(2+) in tricalcium phosphates (TCPs). There are two modifications of α-TCP and β-TCP, and a number of inequivalent Ca sites are present in th...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2015.05.014
更新日期:2015-09-01 00:00:00
abstract:UNLABELLED:Quercetin (3,3',4',5,7-pentahydroxy-flavone) is a flavonoid known for its pharmacological activities, which include antioxidant and anti-inflammatory properties, as well as possible beneficial action on diseases involving bone loss. In this work, we explored the possibility to functionalize hydroxyapatite (H...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2015.12.013
更新日期:2016-03-01 00:00:00
abstract::This study investigates the bone and tissue response to degrading magnesium pin implants in the growing rat skeleton by continuous in vivo microfocus computed tomography (μCT) monitoring over the entire pin degradation period, with special focus on bone remodeling after implant dissolution. The influence of gas releas...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2011.11.008
更新日期:2012-03-01 00:00:00
abstract::The wide variety of diatom frustule shapes and intricate architectures provide viable prototypes to guide the design and fabrication of nanodevices and nanostructured materials for applications ranging from sensors to nanotemplates. In this study, a combined experimental-simulation method was developed to probe the po...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2015.07.028
更新日期:2015-10-01 00:00:00
abstract::A series of poly(2-hydroxyethyl methacrylate) (pHEMA) hydrogels containing cross-linked β-cyclodextrin-hyaluronan (β-CD-crHA), with tear protein adsorption resistance and sustained drug delivery, were developed as contact lens materials for eye diseases. β-CD-HA was synthesized from aminated β-CD and HA and then cross...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2020.04.002
更新日期:2020-07-01 00:00:00
abstract::The effects of a biphasic mineralized collagen scaffold (BCS) containing intrafibrillar silica and apatite on osteogenesis of mouse mesenchymal stem cells (mMSCs) and inhibition of receptor activator of nuclear factor κB ligand (RANKL)-mediated osteoclastogenesis were investigated in the present study. mMSCs were cult...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2015.03.012
更新日期:2015-06-01 00:00:00
abstract::Magnetic N-benzyl-O-carboxymethylchitosan nanoparticles were synthesized through incorporation and in situ methods and characterized by Fourier transform infrared spectroscopy, X-ray diffraction, differential scanning calorimetry, and magnetization measurements. Indomethacin was incorporated into the nanoparticles via...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2011.05.001
更新日期:2011-08-01 00:00:00
abstract::Cationic polymer-based vectors have been considered a promising strategy in gene therapy area due to their inherent ability to condense genetic material and successfully transfect cells. However, they usually exhibit high cytotoxicity. In this work, it is proposed the use of a tailor-made gene carrier based on a tri-b...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2016.10.015
更新日期:2017-01-01 00:00:00
abstract::Sorafenib is a first-line drug for hepatocellular carcinoma (HCC). Autophagy has been shown to facilitate sorafenib resistance. miR-375 has been shown to be an inhibitor of autophagy. In this study, miR-375 and sorafenib were co-loaded into calcium carbonate nanoparticles with lipid coating (miR-375/Sf-LCC NPs). The n...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2018.03.022
更新日期:2018-05-01 00:00:00
abstract::Human-induced pluripotent stem cell (hiPSC)-derived hepatocytes (iHEP) offer an attractive alternative to primary human hepatocytes (PHH) for drug toxicity studies, as PHHs are limited in supply, vary in their metabolic activity between donors, and rapidly lose their functionality in vitro. However, one of the major d...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2019.07.047
更新日期:2019-09-01 00:00:00
abstract::Calcium phosphate cements (CPCs) are highly valuable materials for filling bone defects and bone augmentation by minimal invasive application via percutaneous injection. In the present study some key features were significantly improved by developing a novel injectable ready-to-use calcium phosphate cement based on wa...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2012.12.017
更新日期:2013-04-01 00:00:00
abstract::Flt1 peptide of GNQWFI is an antagonistic peptide for vascular endothelial growth factor receptor 1 (VEGFR1 or Flt1). In this work, Flt1 peptide-hyaluronate (HA) conjugates were successfully synthesized and the resulting micelle-like nanoparticles were exploited to encapsulate genistein, an inhibitor of tyrosine-speci...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2012.07.016
更新日期:2012-11-01 00:00:00
abstract:UNLABELLED:Porous titanium implants are widely used in dental, orthopaedic and otorhinolaryngology fields to improve implant integration to host tissue. A possible step further to improve the integration with the host is the incorporation of autologous cells in porous titanium structures via cell-laden hydrogels. Fast ...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2016.01.023
更新日期:2016-03-01 00:00:00
abstract::N-glycans on IgG and IgM antibodies (Ab) facilitate Ab-mediated crosslinking of viruses and nanoparticles to the major structural elements of mucus and basement membranes. Nevertheless, the chemical moieties in these biological hydrogel matrices to which Ab can bind remain poorly understood. To gain insights into the ...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2020.03.002
更新日期:2020-04-15 00:00:00
abstract::Peripheral arterial disease differentially affects the superficial femoral (SFA) and the popliteal (PA) arteries, but their morphometric, structural, mechanical, and physiologic differences are poorly understood. SFAs and PAs from 125 human subjects (age 13-92, average 52±17 years) were compared in terms of radii, wal...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2020.11.025
更新日期:2021-02-01 00:00:00
abstract::A recombinant red fluorescent protein, DsRed, was chosen as a model protein to prepare a protein-encapsulated bioaerogel, DsRed-SAG. It was prepared using sol-gel polymerization of tetraethyl orthosilicate (TEOS) with an ionic liquid as the solvent and pore-forming agent. The DsRed-SAG bioaerogel was characterized by ...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2007.10.007
更新日期:2008-05-01 00:00:00
abstract::We have developed a class of peptide amphiphile (PA) molecules that self-assemble into three-dimensional nanofiber networks under physiological conditions in the presence of polyvalent metal ions. The assembly can be triggered by adding PA solutions to cell culture media or other synthetic physiological fluids contain...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2005.04.002
更新日期:2005-07-01 00:00:00
abstract::The use of human mesenchymal stromal cells (hMSC) for treating diseased tissues with poor vascularization has received significant attention, but low cell survival has hampered its translation to the clinic. Bioglasses and glass-ceramics have also been suggested as therapeutic agents for stimulating angiogenesis in so...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2017.12.009
更新日期:2018-02-01 00:00:00
abstract:UNLABELLED:We show with laboratory experiments that self-assembled mineral tube formation involving precipitation around a templating jet of fluid - a mechanism well-known in the physical sciences from the tubular growth of so-called chemical gardens - functions with carbonates, and we analyse the microstructures and c...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2016.07.005
更新日期:2016-10-01 00:00:00
abstract::Biphasic calcium phosphates (BCPs) are bioceramics composed of hydroxyapatite (HAp, Ca10(PO4)6(OH)2) and beta-Tricalcium Phosphate (β-TCP, Ca3(PO4)2). Because their chemical and mineral composition closely resembles that of the mineral component of bone, they are potentially interesting candidates for bone repair surg...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2016.12.011
更新日期:2017-03-01 00:00:00
abstract::Photodynamic therapy (PDT) generates highly toxic reactive oxygen species (ROS) during noninvasive cancer treatment. MutT homolog 1 (MTH1) protein is a DNA oxidative damage repair protease and suppressing its function may provide a strategy to enhance PDT efficacy by improving cellular sensitivity to ROS. A nanopartic...
journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2020.04.009
更新日期:2020-06-01 00:00:00