Messenger RNA delivery into Sertoli cells restores fertility to congenitally infertile male mice

Male infertility often results from impaired interactions between germ cells and Sertoli cells. While in vitro fertilization and intracytoplasmic sperm injection are widely used, their success depends on the presence of haploid germ cells. Gene therapy remains challenging due to concerns about germline transmission. The mRNA offers a safer option, as its short-life reduces this risk. Here, we show that mRNA delivery into mouse testes restores fertility in a genetic model of infertility. Injected mRNA was specifically expressed in Sertoli cells; although it triggered an innate immune response, spermatogenesis resumed without major side effects. Delivery of naked Cldn11 mRNA into Cldn11-deficient mice, which have meiotic defects due to defective blood-testis barrier, allowed progression from spermatocytes to spermatids. Fertile offspring with normal imprinting were produced via microinsemination. These findings demonstrate the potential of mRNA-based therapy for treating male infertility by targeting testicular somatic cells, without introducing genetic material into the germline.