Core polymer optimization of ternary siRNA nanoparticles enhances in vivo safety, pharmacokinetics, and tumor gene silencing

Patel, Shrusti S.; Hoogenboezem, Ella N.; Yu, Fang; DeJulius, Carlisle; Fletcher, R. Brock; Sorets, Alexander; Cherry, Fiona K.; Lo, Justin H.; Bezold, Mariah G.; Francini, Nora; d’Arcy, Richard; Cook, Rebecca S.; Duvall, Craig L.

doi:10.1016/j.biomaterials.2023.122098

Cited by 11 publications

(7 citation statements)

References 57 publications

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“…This shift from diffuse to punctate is a useful method for quantifying endosomal escape of therapeutic formulations. 61,62 We chose to test uptake and endosome escape effects as a function of both the number of polymeric repeat units and the %BMA of the DB block of PEGDB. Prior work by Kelly et al demonstrated that the ratio of DMAEMA (cationic) to BMA (hydrophobic) affected both the stability and activity of porous silicon nanoparticles, highlighting 40% BMA (40B) and 50% BMA (50B) as the lead candidates.…”

Section: Resultsmentioning

confidence: 99%

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Nonviral In Vivo Delivery of CRISPR-Cas9 Using Protein-Agnostic, High-Loading Porous Silicon and Polymer Nanoparticles

Fletcher,

Stokes,

Kelly

et al. 2023

ACS Nano

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The complexity of CRISPR machinery is a challenge to its application for nonviral in vivo therapeutic gene editing. Here, we demonstrate that proteins, regardless of size or charge, efficiently load into porous silicon nanoparticles (PSiNPs). Optimizing the loading strategy yields formulations that are ultrahigh loading>40% cargo by volumeand highly active. Further tuning of a polymeric coating on the loaded PSiNPs yields nanocomposites that achieve colloidal stability under cryopreservation, endosome escape, and gene editing efficiencies twice that of the commercial standard Lipofectamine CRISPRMAX. In a mouse model of arthritis, PSiNPs edit cells in both the cartilage and synovium of knee joints, and achieve 60% reduction in expression of the therapeutically relevant MMP13 gene. Administered intramuscularly, they are active over a broad dose range, with the highest tested dose yielding nearly 100% muscle fiber editing at the injection site. The nanocomposite PSiNPs are also amenable to systemic delivery. Administered intravenously in a model that mimics muscular dystrophy, they edit sites of inflamed muscle. Collectively, the results demonstrate that the PSiNP nanocomposites are a versatile system that can achieve high loading of diverse cargoes and can be applied for gene editing in both local and systemic delivery applications.

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Section: Resultsmentioning

confidence: 99%

“…The Gal8 reporter has diffuse cytosolic YFP expression that becomes concentrated around disrupted endosomes. This shift from diffuse to punctate is a useful method for quantifying endosomal escape of therapeutic formulations. , …”

Section: Resultsmentioning

confidence: 99%

Nonviral In Vivo Delivery of CRISPR-Cas9 Using Protein-Agnostic, High-Loading Porous Silicon and Polymer Nanoparticles

Fletcher,

Stokes,

Kelly

et al. 2023

ACS Nano

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“…3–5 Many of these advances utilize pH-responsive polymers to facilitate the endosomal escape and cytosolic delivery of their therapeutic payloads. 6–13 These systems typically exploit the pH drop from 7.4 to 5.8 that occurs during endolysosomal acidification to protonate amino groups within the polymer backbone and/or side chains. As the amines become protonated, the polymer develops a net-positive charge, stimulating interaction with the negatively charged endosomal membrane.…”

Section: Introductionmentioning

confidence: 99%

Engineering endosomolytic nanocarriers of diverse morphologies using confined impingement jet mixing

Pagendarm,

Stone,

Kimmel

et al. 2023

Nanoscale

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“…Polymeric nanocarriers with good stability, siRNA loading, protection of siRNA from degradation, and low immunogenicity have attracted increasing interest for siRNA delivery, − among which polymersomes, having a cavity structure similar to liposomes and tailorable size, morphology, and functions, are unique and versatile. − Yang et al reported that poly( N -vinylpyrrolidone)- b -poly(dimethylsiloxane)- b -poly( N -vinylpyrrolidone) polymersomes loaded with PARP1 siRNA achieved efficient PARP1 silencing and prolonged survival of breast tumor-bearing mice . Kataoka et al found that poly(ethylene glycol)- b -poly[ N -(5-aminopentyl)-α,β-aspartamide] copolymers could self-assemble with siRNA to form polyion-complexed vesicles and achieve efficient siRNA delivery to cultured cells .…”

Section: Introductionmentioning

confidence: 99%

Bioresponsive Chimaeric Polymersomes Mediate Sustained and Liver-Specific siRNA Transfection In Vivo

Huang,

Wang,

et al. 2023

Biomacromolecules

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The silencing of disease-causing genes with small interfering RNA (siRNA) offers a particularly effective therapeutic strategy for different disorders; however, its clinical efficacy relies on the development of nontoxic and tissue-specific delivery vehicles. Herein, we report that bioresponsive chimaeric polymersomes (BCP) with short poly(ethylenimine) as inner shell mediate highly efficacious, sustained, and liver-specific siRNA transfection in vivo. BCP exhibited remarkable encapsulation efficiencies of siRNA (95–100%) at siRNA-feeding contents of 15–25 wt %, to afford stable, small-sized (55–64 nm), and neutral-charged BCP-siRNA. siApoB-Loaded BCP (BCP-siApoB) outperformed lipofectamine counterparts and silenced 93% of ApoB mRNA in HepG2 cells at 50 nM siApoB without inducing cytotoxicity. Intriguingly, the in vivo studies using wild-type C57BL/6 mice revealed that BCP-siApoB preferentially accumulated in the liver, and a single dose of 4.5 mg/kg achieved over 90% downregulation of ApoB mRNA for at least 10 days. The systemic administration of BCP-siApoB at 4.5 mg/kg every 2 weeks or 1.5 mg/kg weekly in diet-induced obese mice could also achieve up to 80% silencing of ApoB mRNA. The liver specificity and silencing efficacy of BCP-siApoB could further be improved by decorating it with the trivalent N-acetylgalactosamine (TriGalNAc) ligand. These bioresponsive and liver-specific chimaeric polymersomes provide an enabling technology for siRNA therapy of various liver-related diseases.

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Core polymer optimization of ternary siRNA nanoparticles enhances in vivo safety, pharmacokinetics, and tumor gene silencing

Cited by 11 publications

References 57 publications

Nonviral In Vivo Delivery of CRISPR-Cas9 Using Protein-Agnostic, High-Loading Porous Silicon and Polymer Nanoparticles

Nonviral In Vivo Delivery of CRISPR-Cas9 Using Protein-Agnostic, High-Loading Porous Silicon and Polymer Nanoparticles

Engineering endosomolytic nanocarriers of diverse morphologies using confined impingement jet mixing

Bioresponsive Chimaeric Polymersomes Mediate Sustained and Liver-Specific siRNA Transfection In Vivo

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