Sperm and offspring production in a nonobstructive azoospermia mouse model via testicular mRNA delivery using lipid nanoparticles

Mashiko, Daisuke; Emori, Chihiro; Hatanaka, Yuki et al.

Proceedings of the National Academy of Sciences of the United States of America, 2025, 122(42), e2516573122

アクセス数:37件（2026-02-05 19:10 集計）

固定URL: https://hdl.handle.net/11094/103681

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タイトル
Sperm and offspring production in a nonobstructive azoospermia mouse model via testicular mRNA delivery using lipid nanoparticles
著者
ORCID
0000-0003-3927-3076 0000-0003-3927-3076
researchmap permalink
mashikodaisuke mashikodaisuke
Scopus Author ID
55953432500 55953432500
著者名
Mashiko, Daisuke
NRID
1000010868136 1000010868136
ORCID
0000-0001-8040-2517 0000-0001-8040-2517
researchmap permalink
cemori cemori
Scopus Author ID
55937469900 55937469900
著者名
Emori, Chihiro
NRID
1000070719450 1000070719450
ORCID
0000-0003-1339-8612 0000-0003-1339-8612
researchmap permalink
y.hatanaka y.hatanaka
Scopus Author ID
36494602600 36494602600
著者名
Hatanaka, Yuki
NRID
1000010636830 1000010636830
researchmap permalink
daisukem daisukem
Scopus Author ID
35315737900 35315737900
著者名
Motooka, Daisuke
著者名
Pan, Chen
ORCID
0000-0001-6300-4234 0000-0001-6300-4234
Scopus Author ID
57218423045 57218423045
著者名
Kaneda, Yuki
著者名
Matzuk, Martin M.
NRID
1000020304066 1000020304066
ORCID
0000-0001-9859-6217 0000-0001-9859-6217
researchmap permalink
read0054910 read0054910
Scopus Author ID
16689054500 16689054500
著者名
Ikawa, Masahito
キーワード等
azoospermia
germline therapy
lipid nanoparticle
LNP therapy
sterility
内容
Mashiko D., Emori C., Hatanaka Y., et al. Sperm and offspring production in a nonobstructive azoospermia mouse model via testicular mRNA delivery using lipid nanoparticles. Proceedings of the National Academy of Sciences of the United States of America 122, e2516573122 (2025); https://doi.org/10.1073/pnas.2516573122.
抄録
Microsurgical testicular sperm extraction (microTESE) with intracytoplasmic sperm injection (ICSI) represents the current standard treatment for nonobstructive azoospermia (NOA). However, cures remain unavailable for NOA patients lacking retrievable haploid cells. mRNA supplementation could be a potential treatment for genetic defects leading to impaired spermatogenesis. Lipid nanoparticles (LNPs) have emerged as mRNA delivery vehicles with minimal risk of genome integration; however, their ability to selectively deliver mRNA to specific cell types remains limited. To overcome this, microRNA (miRNA) target sequences were incorporated into mRNA constructs to restrict expression specifically to germ cells. Using pyruvate dehydrogenase E1 subunit alpha 2 (PDHA2) knockout mice as an NOA model with meiotic arrest, we demonstrate that LNP-mediated delivery of Pdha2 mRNA enables the resumption and completion of meiosis, restores sperm production, and facilitates the generation of healthy fertile offspring via ICSI. Whole-genome sequencing of the offspring confirmed the absence of large-scale genomic abnormalities. Our results provide proof of concept for a safe and effective chemically synthesized LNP-based mRNA therapy with miRNA-regulated germ cell specificity, offering a promising therapeutic approach to treating male infertility caused by spermatogenesis arrest.
出版者
National Academy of Sciences
収録物名
Proceedings of the National Academy of Sciences of the United States of America
巻(号)
122(42)
ページ
e2516573122
刊行年月
2025-10-13
言語
英語
ハンドルURL
https://hdl.handle.net/11094/103681
PISSN
00278424
eISSN
10916490
関連情報 (isIdenticalTo)
DOI (出版社版)
https://doi.org/10.1073/pnas.2516573122
アクセス権
open access
権利情報
This article is licensed under a Creative Commons Attribution 4.0 International License.
出版タイプ
Version of Record
カテゴリ
学術雑誌論文 Journal Article