Scheme 1.

Schematic illustration for the nanoparticle fabrication and therapeutic workflow. The PICASSO is self-assembled from the multifunctional shell and CRISPRa polyplex electrostatic interaction and demonstrated on demand responses to the sequential physiological barriers in vivo, leading to efficient CRISPR/dCas9-mediated endogenous transcriptional activation without introducing genome changes and exogenous gene. This ability breaks the restrictions of gene size and type in genetic-based therapeutics and opens new avenue for oncological treatment.