Comparison of DLin-MC3-DMA and ALC-0315 for siRNA Delivery to Hepatocytes and Hepatic Stellate Cells

Ferraresso, Francesca; Strilchuk, Amy W.; Juang, Lih Jiin; Poole, Lauren G.; Luyendyk, James P.; Kastrup, Christian J.

doi:10.1021/acs.molpharmaceut.2c00033

Cited by 52 publications

(32 citation statements)

References 52 publications

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“…S7), low protein expression and high platelet activation made these undesirable transfection reagents. ALC-0315, which is a potent ionizable LNP in most settings ( 24 , 25 ), gave low expression. Apart from KC2, no ionizable lipid in combination with DSPC achieved higher protein expression than MC3, and only lipids with an acid dissociation constant (pKa) between 6.5 and 6.7 enabled NanoLuc expression when transfected at a pH of 6.5 (fig.…”

Section: Resultsmentioning

confidence: 99%

Genetically engineered transfusable platelets using mRNA lipid nanoparticles

Leung,

Strong,

Badior

et al. 2023

Sci. Adv.

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Platelet transfusions are essential for managing bleeding and hemostatic dysfunction and could be expanded as a cell therapy due to the multifunctional role of platelets in various diseases. Creating these cell therapies will require modifying transfusable donor platelets to express therapeutic proteins. However, there are currently no appropriate methods for genetically modifying platelets collected from blood donors. Here, we describe an approach using platelet-optimized lipid nanoparticles containing mRNA (mRNA-LNP) to enable exogenous protein expression in human and rat platelets. Within the library of mRNA-LNP tested, exogenous protein expression did not require nor correlate with platelet activation. Transfected platelets retained hemostatic function and accumulated in regions of vascular damage after transfusion into rats with hemorrhagic shock. We expect this technology will expand the therapeutic potential of platelets.

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Section: Resultsmentioning

confidence: 99%

Genetically engineered transfusable platelets using mRNA lipid nanoparticles

Leung,

Strong,

Badior

et al. 2023

Sci. Adv.

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“…The formed complex can be used to co-deliver mRNA within cationic amphiphilic drugs-assisted LNPs for various applications ( Bogaert et al, 2022 ). The approved LNP-based therapeutic formulations such as Patisiran (Alnylam), Elasomeran (Moderna) use similar ratios (50:10:38.5:1.5) of ILs, helper lipid (DSPC), cholesterol and polyethylene glycol lipids ( Suzuki and Ishihara, 2021 ; Ferraresso et al, 2022 ). The said molar ratio has been reported by many studies as optimum and highly potent ( Carrasco et al, 2021 ; Suzuki et al, 2022 ).…”

Section: Nanoparticles (Nps) Used For the Sirna Therapy Of Covid-19mentioning

confidence: 99%

Potential of siRNA in COVID-19 therapy: Emphasis on in silico design and nanoparticles based delivery

Fopase

Panda

Rajendran

et al. 2023

Front. Bioeng. Biotechnol.

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Small interfering RNA (siRNA)-mediated mRNA degradation approach have imparted its eminence against several difficult-to-treat genetic disorders and other allied diseases. Viral outbreaks and resulting pandemics have repeatedly threatened public health and questioned human preparedness at the forefront of drug design and biomedical readiness. During the recent pandemic caused by the SARS-CoV-2, mRNA-based vaccination strategies have paved the way for a new era of RNA therapeutics. RNA Interference (RNAi) based approach using small interfering RNA may complement clinical management of the COVID-19. RNA Interference approach will primarily work by restricting the synthesis of the proteins required for viral replication, thereby hampering viral cellular entry and trafficking by targeting host as well as protein factors. Despite promising benefits, the stability of small interfering RNA in the physiological environment is of grave concern as well as site-directed targeted delivery and evasion of the immune system require immediate attention. In this regard, nanotechnology offers viable solutions for these challenges. The review highlights the potential of small interfering RNAs targeted toward specific regions of the viral genome and the features of nanoformulations necessary for the entrapment and delivery of small interfering RNAs. In silico design of small interfering RNA for different variants of SARS-CoV-2 has been discussed. Various nanoparticles as promising carriers of small interfering RNAs along with their salient properties, including surface functionalization, are summarized. This review will help tackle the real-world challenges encountered by the in vivo delivery of small interfering RNAs, ensuring a safe, stable, and readily available drug candidate for efficient management of SARS-CoV-2 in the future.

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“…SM-102 is a synthetic and ionizable amino lipid that has been widely used in combination with other lipids in the formation of lipid nanoparticles [ 50 , 51 , 52 ]. Formulations containing SM-102 have been noticeably used in the development of lipid nanoparticles for the delivery of mRNA-based vaccines.…”

Section: Hys (V) Behavior Residing In Er...mentioning

confidence: 99%

Effective Perturbations by Small-Molecule Modulators on Voltage-Dependent Hysteresis of Transmembrane Ionic Currents

Cho

et al. 2022

IJMS

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The non-linear voltage-dependent hysteresis (Hys(V)) of voltage-gated ionic currents can be robustly activated by the isosceles-triangular ramp voltage (Vramp) through digital-to-analog conversion. Perturbations on this Hys(V) behavior play a role in regulating membrane excitability in different excitable cells. A variety of small molecules may influence the strength of Hys(V) in different types of ionic currents elicited by long-lasting triangular Vramp. Pirfenidone, an anti-fibrotic drug, decreased the magnitude of Ih’s Hys(V) activated by triangular Vramp, while dexmedetomidine, an agonist of α2-adrenoceptors, effectively suppressed Ih as well as diminished the Hys(V) strength of Ih. Oxaliplatin, a platinum-based anti-neoplastic drug, was noted to enhance the Ih’s Hys(V) strength, which is thought to be linked to the occurrence of neuropathic pain, while honokiol, a hydroxylated biphenyl compound, decreased Ih’s Hys(V). Cell exposure to lutein, a xanthophyll carotenoid, resulted in a reduction of Ih’s Hys(V) magnitude. Moreover, with cell exposure to UCL-2077, SM-102, isoplumbagin, or plumbagin, the Hys(V) strength of erg-mediated K+ current activated by triangular Vramp was effectively diminished, whereas the presence of either remdesivir or QO-58 respectively decreased or increased Hys(V) magnitude of M-type K+ current. Zingerone, a methoxyphenol, was found to attenuate Hys(V) (with low- and high-threshold loops) of L-type Ca2+ current induced by long-lasting triangular Vramp. The Hys(V) properties of persistent Na+ current (INa(P)) evoked by triangular Vramp were characterized by a figure-of-eight (i.e., ∞) configuration with two distinct loops (i.e., low- and high-threshold loops). The presence of either tefluthrin, a pyrethroid insecticide, or t-butyl hydroperoxide, an oxidant, enhanced the Hys(V) strength of INa(P). However, further addition of dapagliflozin can reverse their augmenting effects in the Hys(V) magnitude of the current. Furthermore, the addition of esaxerenone, mirogabalin, or dapagliflozin was effective in inhibiting the strength of INa(P). Taken together, the observed perturbations by these small-molecule modulators on Hys(V) strength in different types of ionic currents evoked during triangular Vramp are expected to influence the functional activities (e.g., electrical behaviors) of different excitable cells in vitro or in vivo.

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Comparison of DLin-MC3-DMA and ALC-0315 for siRNA Delivery to Hepatocytes and Hepatic Stellate Cells

Cited by 52 publications

References 52 publications

Genetically engineered transfusable platelets using mRNA lipid nanoparticles

Genetically engineered transfusable platelets using mRNA lipid nanoparticles

Potential of siRNA in COVID-19 therapy: Emphasis on in silico design and nanoparticles based delivery

Effective Perturbations by Small-Molecule Modulators on Voltage-Dependent Hysteresis of Transmembrane Ionic Currents

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