Regulation of CRISPR-Cas9 functions in vivo is conducive to developing precise therapeutic genome editing. Here, we report a CRISPR-Cas9 prodrug nanosystem (termed NanoProCas9), which combines the targeted delivery and the conditional activation of CRISPR-Cas9 for the precision therapy of inflammatory bowel disease. NanoProCas9 is composed of (i) cationic poly(β-amino ester) (PBAE) capable of complexing plasmid DNA encoding destabilized Cas9 (dsCas9) nuclease, (ii) a layer of biomimetic cell membrane coated on PBAE/plasmid nanocomplexes for the targeted delivery of PBAE/dsCas9 complexes, and (iii) the stimuli-responsive precursory molecules anchored on the exofacial membrane. The systemic administration of NanoProCas9 enables the targeted delivery of dsCas9 plasmid into inflammatory lesions, where the precursory small molecule can be activated by ROS signals to stabilize expressed dsCas9, thereby activating Cas9 function for inflammatory genome editing. The proposed “genome-editing prodrug” presents a proof-of-concept example to precisely regulate CRISPR-Cas9 functions by virtue of particular pathological stimuli in vivo.
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