Ionizable lipid nanoparticles deliver mRNA to pancreatic β cells via macrophage-mediated gene transfer.
Jilian R MelamedSaigopalakrishna S YerneniMariah L ArralSamuel T LoPrestiNamit ChaudharyAnuradha SehrawatHiromi MuramatsuMohamad-Gabriel AlamehNorbert PardiDrew WeissmanGeorge K GittesKathryn A WhiteheadPublished in: Science advances (2023)
Systemic messenger RNA (mRNA) delivery to organs outside the liver, spleen, and lungs remains challenging. To overcome this issue, we hypothesized that altering nanoparticle chemistry and administration routes may enable mRNA-induced protein expression outside of the reticuloendothelial system. Here, we describe a strategy for delivering mRNA potently and specifically to the pancreas using lipid nanoparticles. Our results show that delivering lipid nanoparticles containing cationic helper lipids by intraperitoneal administration produces robust and specific protein expression in the pancreas. Most resultant protein expression occurred within insulin-producing β cells. Last, we found that pancreatic mRNA delivery was dependent on horizontal gene transfer by peritoneal macrophage exosome secretion, an underappreciated mechanism that influences the delivery of mRNA lipid nanoparticles. We anticipate that this strategy will enable gene therapies for intractable pancreatic diseases such as diabetes and cancer.
Keyphrases
- binding protein
- induced apoptosis
- type diabetes
- fatty acid
- genome wide
- cell cycle arrest
- adipose tissue
- cardiovascular disease
- metabolic syndrome
- dna methylation
- squamous cell carcinoma
- papillary thyroid
- dendritic cells
- cell proliferation
- glycemic control
- young adults
- cell death
- high glucose
- walled carbon nanotubes
- skeletal muscle
- drug induced
- squamous cell