Challenges in delivery systems for CRISPR-based genome editing and opportunities of nanomedicine

Abstract

The CRISPR-based genome editing technology has opened extremely useful strategies in biological research and clinical therapeutics, thus attracting great attention with tremendous progress in the past decade. Despite its robust potential in personalized and precision medicine, the CRISPR-based gene editing has been limited by inefficient in vivo delivery to the target cells and by safety concerns of viral vectors for clinical setting. In this review, recent advances in tailored nanoparticles as a means of non-viral delivery vector for CRISPR/Cas systems are thoroughly discussed. Unique characteristics of the nanoparticles including controllable size, surface tunability, and low immune response lead considerable potential of CRISPR-based gene editing as a translational medicine. We will present an overall view on essential elements in CRISPR/ Cas systems and the nanoparticle-based delivery carriers including advantages and challenges. Perspectives to advance the current limitations are also discussed toward bench-to-bedside translation in engineering aspects.

Targeted Therapies in Cancer: To Be or Not to Be, Selective

“…In the last few years, a novel approach to target proteins in cancer was developed not by blocking their enzymatic activity but in reducing their levels by targeted degradation [ 69 ]. This goal is similar to those of siRNA or genome engineering [ 70 ], but there are still tremendous limitations to those approaches, [ 71 , 72 , 73 ] such as nonreversibility of gene editing. This new strategy of targeted protein degradation uses small molecules (taking advantage of their oral availability) but tag them with unique cellular signals able to trigger an intracellular degradation process of the bound protein via the ubiquitin-proteasomal machinery [ 74 ].…”

Context-Responsive Nanoparticle Derived from Synthetic Zwitterionic Ionizable Phospholipids in Targeted CRISPR/Cas9 Therapy for Basal-like Breast Cancer

“…Moreover, the delivery of genome-editing elements to the area of interest without causing off-target side effects remains a significant challenge. The scenario is complicated because there is a stark difference between conventional single-component nucleic acid system and multicomponent CRISPR delivery vehicles. , For single-component systems, once introduced into the cells, plasmid DNA or mRNA can express the desired protein and exert its biological function. If siRNA, microRNAs (miRNAs), or antisense oligonucleotides (ASOs) are to exert a biological function, they must interact with the RNA-induced silencing complex (RISC) or the Ribonuclease H, but the target cells express these components natively, so no additional therapeutic molecules are required.…”

A modular strategy for extracellular vesicle-mediated CRISPR-Cas9 delivery through aptamer-based loading and UV-activated cargo release

“…Whereas the CRISPR-Cas9 toolbox has been extensively characterized and expanded over the last decade, intracellular delivery remains one of the major hurdles for therapeutic applications. Efficient intracellular delivery of the Cas9 RNP complex is hampered due to its large size, negative charge, and immunogenicity 13 . To this end, various intracellular delivery strategies have been employed to facilitate Cas9 RNP delivery, including viral vectors, lipid nanoparticles (LNPs), polymers, and cell penetrating peptides (CPPs) [14][15][16][17] .…”