2. Academic Validation
  3. Cholesterol-Amino-Phosphate (CAP) Derived Lipid Nanoparticles for Delivery of Self-Amplifying RNA and Restoration of Spermatogenesis in Infertile Mice

Cholesterol-Amino-Phosphate (CAP) Derived Lipid Nanoparticles for Delivery of Self-Amplifying RNA and Restoration of Spermatogenesis in Infertile Mice

  • Adv Sci (Weinh). 2023 Apr;10(11):e2300188. doi: 10.1002/advs.202300188.
Shi Du 1,  Wenqing Li 1,  Yuebao Zhang 1,  Yonger Xue 1,  Xucheng Hou 1,  Jingyue Yan 1,  Jeffrey Cheng 1,  Binbin Deng 2,  David W McComb 2 3,  Jennifer Lin 4,  Hong Zeng 4,  Xiaolin Cheng 5,  Darrell J Irvine 6 7 8 9 10,  Ron Weiss 6 11 12,  Yizhou Dong 1 13 14
Affiliations

Affiliations

  • 1 Division of Pharmaceutics & Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, 43210, USA.
  • 2 Center for Electron Microscopy and Analysis, The Ohio State University, Columbus, OH, 43212, USA.
  • 3 Department of Materials Science and Engineering, The Ohio State University, Columbus, OH, 43210, USA.
  • 4 Transgenic, Knockout, and Tumor Model Center, Stanford University School of Medicine, Stanford, CA, 94305, USA.
  • 5 Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH, 43210, USA.
  • 6 Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
  • 7 Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
  • 8 Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
  • 9 Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, 02139, USA.
  • 10 Howard Hughes Medical Institute, Chevy Chase, MD, 20815, USA.
  • 11 Synthetic Biology Center, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
  • 12 Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
  • 13 Department of Biomedical Engineering, Center for Clinical and Translational Science, Comprehensive Cancer Center, Dorothy M. Davis Heart & Lung Research Institute, Department of Radiation Oncology, Center for Cancer Engineering, Center for Cancer Metabolism, Pelotonia Institute for Immune-Oncology, The Ohio State University, Columbus, OH, 43210, USA.
  • 14 Icahn Genomics Institute, Precision Immunology Institute, Department of Oncological Sciences, Tisch Cancer Institute, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
PMID: 36748274 DOI: 10.1002/advs.202300188
Abstract

Male infertility caused by genetic mutations is an important type of infertility. Currently, there is no reliable method in the clinic to address this medical need. The emergence of mRNA therapy provides a possible strategy for restoring mutant genes in the reproductive system. However, effective delivery of mRNA to spermatocytes remains a formidable challenge. Here a series of cholesterol-amino-phosphate (CAP) lipids are reported by integrating three bioactive moieties into a geometric structure, which is favorable for mRNA delivery. The results demonstrate that CAP-derived lipid nanoparticles (CAP LNPs) can deliver RNA including traditional mRNA and self-amplifying RNA (saRNA) encoding DNA Meiotic Recombinase 1 (Dmc1) protein in spermatocytes and treat male infertility caused by the Dmc1 gene mutation. Notably, the delivery efficiency of CAP LNPs is significantly higher than that of the MC3 and ALC-0315 LNPs, which is consistent with the design of CAP molecules. More importantly, a single injection of CAP LNPs-saRNA can produce Dmc1 protein for an extended period, which restores the spermatogenesis in the Dmc1 gene knockout mouse model. Overall, this study proves the concept of LNPs for the delivery of mRNA to spermatocytes, which provides a unique method to probe male infertility caused by the genetic mutation.

Keywords

lipid nanoparticles; mRNA therapy; male infertility; self-amplifying RNA; spermatocytes delivery.

Figures
Products