Tumor microenvironment based stimuli-responsive CRISPR/Cas delivery systems: A viable platform for interventional approaches.

The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein (Cas) systems have emerged as robust tools in cancer gene therapy due to their simplicity and versatility. Nevertheless, the genome editing efficiency in tumor sites and the clinical applications of CRISPR/Cas have been compromised by non-specific delivery and genotoxicity. Recently, intelligent delivery systems incorporating sensitive materials in response to endogenous stimuli of the tumor microenvironment (TME) have represented viable platforms for tumor-specific genome editing and reduced side effects of CRISPR/Cas. Spurred by this promising direction, this review first introduces the CRISPR/Cas systems widely employed in cancer therapeutic explorations. Various types of CRISPR/Cas delivery systems sensitive to the stimuli in TME and typical dual-/multiple-responsive CRISPR/Cas carriers are further discussed, emphasizing the correlations between sensitive components and spatiotemporal delivery mechanisms. The genome editing efficiencies of CRISPR/Cas-loaded stimuli-responsive carriers are also summarized both in vitro and in vivo. Collectively, stimuli-responsive CRISPR/Cas delivery systems hold great promise for potent cancer gene therapy.