Transdermal microneedle-assisted ultrasound-enhanced CRISPRa system to enable sono-gene therapy for obesity

Shaoyue Li, Jifeng Yu, Yuting Shen, Bing Xiong, Zhao De, Weichen Xu, Shen Zhang, Xin Guan, Yunyun Liu, Xuexia Shan, Anqi Zhu, Qi Lyu, Yan Fang, Zitong Chen, Haohao Yin (yin.haohao@zs-hospital.sh.cn), Liping Sun (sunliping_s@126.com) and Huixiong Xu (xu.huixiong@zs-hospital.sh.cn)
Additional contact information
Shaoyue Li: Tongji University
Jifeng Yu: Fudan University
Yuting Shen: Fudan University
Bing Xiong: Fudan University
Zhao De: Tongji University
Weichen Xu: Tongji University
Shen Zhang: Tongji University
Xin Guan: Fudan University
Yunyun Liu: Tongji University
Xuexia Shan: Tongji University
Anqi Zhu: Fudan University
Qi Lyu: Fudan University
Yan Fang: Fudan University
Zitong Chen: Fudan University
Haohao Yin: Fudan University
Liping Sun: Tongji University
Huixiong Xu: Fudan University

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract Obesity, a surging global health challenge, necessitates effective, accessible and innovative therapeutic models. Here we develop a spatiotemporally controllable microneedle (MN) drug delivery platform for sono-gene therapy to fight obesity. The platform delivers the methoxy polyethylene glycol-polyethyleneimine (mPEG-PEI) modified metal-organic frameworks (MOFs) sonosensitizer and the clustered regularly interspaced short palindromic repeats-activating (CRISPRa)/CRISPRa-uncoupling protein 1 (UCP1) system intradermally to adipocytes. Overall, this therapy platform is capable of achieving two major strategies of “annihilation” and “countermeasure”: one is to kill redundant white adipocytes by sonodynamic therapy, and the other is to promote the browning of white adipocytes through the controllable release of CRISPRa-UCP1 system and sonodynamic effect. Obese male mice treated with this sono-gene therapy shows significant ameliorate in glucose tolerance and insulin sensitivity, successfully achieves weight loss and restrains weight rebound. This study may enable a standard treatment paradigm for sono-gene therapy of obesity and other metabolic diseases.

Date: 2025
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DOI: 10.1038/s41467-025-56755-4

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