Rational Design of Bisphosphonate Lipid-like Materials for mRNA Delivery to the Bone Microenvironment

Xue, Lulu; Gong, Ningqiang; Shepherd, Sarah; Xiong, Xinhong; Liao, Xueyang; Han, Xuexiang; Zhao, Gan; Song, Chao; Huang, Xisha; Zhang, Hanwen; Padilla, Marshall S.; Qin, Jingya; Shi, Yi; Alameh, Mohamad-Gabriel; Pochan, Darrin J.; Wang, Karin; Long, Fanxin; Weissman, Drew; Mitchell, Michael J.

doi:10.1021/jacs.2c02706

Cited by 89 publications

(66 citation statements)

References 80 publications

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“…mRNA encapsulation efficiency of each LNP formulation was calculated using the Quant-iTRiboGreen (Thermo Fisher Scientific, Waltham, MA) assay. 36 LNP samples were diluted to approximately 2 ng μL −1 in microcentrifuge tubes containing either 1× TE buffer or 0.1% (v/v) Triton X-100 (Sigma-Aldrich). LNPs in TE buffer or Triton-X as well as mRNA standards were plated in triplicate in black 96-well plates following which fluorescent RiboGreen reagent was then added in each well.…”

Section: Methodsmentioning

confidence: 99%

RGD peptide-based lipids for targeted mRNA delivery and gene editing applications

et al. 2022

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Section: Methodsmentioning

confidence: 99%

RGD peptide-based lipids for targeted mRNA delivery and gene editing applications

et al. 2022

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“…Xue et al. ( 40 ) developed a bisphosphonate lipid-like material to deliver mRNA into the bone microenvironment. Despite these pioneering achievements, most of the established delivery platforms suffer from different limitations on satisfied RNA delivery.…”

Section: Discussionmentioning

confidence: 99%

Rational polyelectrolyte nanoparticles endow preosteoclast-targeted siRNA transfection for anabolic therapy of osteoporosis

et al. 2023

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Targeted transfection of siRNA to preosteoclasts features the potential of anti-osteoporosis, yet challenge arises from the development of satisfied delivery vehicles. Here, we design a rational core-shell nanoparticle (NP) composed of cationic and responsive core for controlled load and release of small interfering RNA (siRNA) and compatible polyethylene glycol shell modified with alendronate for enhanced circulation and bone-targeted delivery of siRNA. The designed NPs perform well on transfection of an active siRNA (siDcstamp) that interferes Dcstamp mRNA expression, leading to impeded preosteoclast fusion and bone resorption, as well as promoted osteogenesis. In vivo results corroborate the abundant siDcstamp accumulation on bone surfaces and the enhanced trabecular bone mass volume and microstructure in treating osteoporotic OVX mice by rebalancing bone resorption, formation, and vascularization. Our study validates the hypothesis that satisfied transfection of siRNA enables preserved preosteoclasts that regulate bone resorption and formation simultaneously as potential anabolic treatment for osteoporosis.

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“…Recently, virus-like particles (VLPs) have been used for in vivo editing of murine liver or retina ( 49 ). Furthermore, nonviral vehicles based on lipid nanoparticles (LNPs) for mRNA delivery ( 50 , 51 ) hold great promise for in vivo HSC genome editing. However, these new approaches also face the hurdles accounted with intravascular administration of viral vectors — namely, the unproductive sequestration, which requires high vector doses, and the associated acute toxicity.…”

Section: Discussionmentioning

confidence: 99%

In vivo base editing by a single i.v. vector injection for treatment of hemoglobinopathies

Li¹,

Georgakopoulou²,

Newby³

et al. 2022

JCI Insight

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Individuals with -thalassemia or Sickle Cell Disease and hereditary persistence of fetal hemoglobin (HPFH) possessing 30% HbF appear to be symptom-free. Here, we used a non-integrating HDAd5/35++ vector expressing a highly efficient and accurate version of an adenine base editor (ABE8e) to install, in vivo, a -113A>G HPFH mutation in the -globin promoters in "healthy" CD46/-YAC mice carrying the human -globin locus. Our in vivo hematopoietic stem cell (HSC) editing/selection strategy involves only subcutaneous and intravenous injections and does not require myeloablation and HSC transplantation. In vivo HSC base editing in CD46/-YAC mice resulted in >60% -113A>G conversion with 30% -globin of globin expressed in 70% of erythrocytes. Importantly, no off-target editing at sites predicted by CIRCLE-Seq or in silico was detected. Furthermore, no critical alterations in the transcriptome of in vivo edited mice were found by RNA-seq. In vitro, in HSCs from -thalassemia and Sickle Cell Disease patients, transduction with the base editor vector mediated efficient -113 A>G conversion and reactivation of −globin expression with subsequent phenotypic correction of erythroid cells. Because our in vivo base editing strategy is safe and technically simple, it has the potential for clinical application in developing countries where hemoglobinopathies are prevalent. Key points-In vivo HSC transduction of -YAC mice with an ABE8e expressing HDAd5/35++ vector is safe and results in efficient and stable -globin reactivation in ~70% of erythrocytes at levels of 30% of human -globin.-Therapeutic editing is achieved in thalassemia and Sickle Cell Disease patient CD34 + cells with HDAd-EF1.ABE8e, leading to phenotypic correction in in vitro differentiated erythroid cells.

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Rational Design of Bisphosphonate Lipid-like Materials for mRNA Delivery to the Bone Microenvironment

Cited by 89 publications

References 80 publications

RGD peptide-based lipids for targeted mRNA delivery and gene editing applications

RGD peptide-based lipids for targeted mRNA delivery and gene editing applications

Rational polyelectrolyte nanoparticles endow preosteoclast-targeted siRNA transfection for anabolic therapy of osteoporosis

In vivo base editing by a single i.v. vector injection for treatment of hemoglobinopathies

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