p53-Sentinel CRISPR: Real-time DSB Surveillance That Auto-Switches to Nickase/Prime Editing to Prevent Catastrophic Lesions

Engineer a nanoparticle platform that delivers Cas9 nuclease together with a rapid p53 activity reporter and a “fail-safe” switch. If p53 activation crosses a threshold (indicating dangerous DSB stress), the system halts nuclease activity and releases a backup editing modality (Cas9 nickase, base editor, or prime editor) to finish the intended edit without further DSBs. This concept integrates non-viral delivery advances and co-delivery concepts with editing modality switching recommended by mechanistic insights, embedding safety logic directly into the delivery vehicle. It aims to minimize rare but severe on-target catastrophes without compromising edit completion, offering a practical path to safer clinical CRISPR by converting p53 activation into a control signal that redirects editing strategy on the fly.

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