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

We developed a spatiotemporally controllable microneedle (MN) platform for sono-gene therapy to fight obesity. The methoxy polyethylene glycol-polyethyleneimine (mPEG-PEI) modified metal-organic frameworks (MOFs) sonosensitizer encapsulated the clustered regularly interspaced short palindromic repeat-activating (CRISPRa)/CRISPRa-uncoupling protein 1 (UCP1) system, prepared in a MN patch, and delivered intradermally to adipocytes. Overall, this therapy platform 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 showed significant ameliorate in glucose tolerance and insulin sensitivity, successfully achieved weight loss and restrained weight rebound.