Non-invasive control of gene editing in vivo by photoswitchable Cas12f and focused ultrasound.

September 28, 2026| Source: Cell

A spatiotemporally controllable CRISPR-Cas system would be highly desirable for restricting gene editing to specific times and locations in vivo. Ideally, such a system would be compatible with tissue- or cell-type-specific delivery by adeno-associated virus (AAV) and could be controlled from outside the body. However, neither the delivery of controllable CRISPR-Cas systems by single AAV particles nor their noninvasive activation deep within tissue has yet been achieved. In this study, we address both of these limitations. We engineer compact photoswitchable Cas12f (psCas12f) proteins that are co-deliverable with their single guide RNA (sgRNA) in a single AAV particle. We then activate psCas12f in vivo using focused ultrasound (FUS) and mechanoluminescent particles, enabling precise spatiotemporal control. We demonstrate successful gene editing in the targeted skeletal muscle and brain regions of mice using AAV-transduced psCas12f and FUS. In summary, we describe a completely noninvasive method for localized gene editing in vivo.

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