Precisely Targeted Nanoparticles for CRISPR-Cas9 Delivery in Clinical Applications

Clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR-Cas9), an emerging gene-editing technology, has recently gained rapidly increasing attention. However, the lack of efficient delivery vectors to deliver CRISPR-Cas9 to specific cells or tissues has hindered the translation of this biotechnology into clinical applications. Chemically synthesized nanoparticles (NPs), as attractive non-viral delivery platforms for CRISPR-Cas9, have been extensively investigated because of their unique characteristics, such as controllable size, high stability, multi-functionality, bio-responsive behavior, biocompatibility, and versatility in chemistry. In this review, the key considerations for the precise design of chemically synthesized-based nanoparticles include efficient encapsulation, cellular uptake, the targeting of specific tissues and cells, endosomal escape, and controlled release. We discuss cutting-edge strategies to integrate chemical modifications into non-viral nanoparticles that guide the CRISPR-Cas9 genome-editing machinery to specific edits. We also highlighted the rationale of intelligent nanoparticle design. In particular, we have summarized promising functional groups and molecules that can effectively optimize carrier function. In addition, this review focuses on advances in the widespread application of NPs delivery in the biomedical fields to promote the development of safe, specific, and efficient NPs for delivering CRISPR-Cas9 systems, providing references for accelerating their clinical translational applications.