Natural Biopolymer-Based Delivery of CRISPR/Cas9 for Cancer Treatment

Over the last decade, the clustered, regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system has become the most promising gene editing tool and is broadly utilized to manipulate the gene for disease treatment, especially for cancer, which involves multiple genetic alterations. Typically, CRISPR/Cas9 machinery is delivered in one of three forms: DNA, mRNA, or ribonucleoprotein. However, the lack of efficient delivery systems for these macromolecules confined the clinical breakthrough of this technique. Therefore, a variety of nanomaterials have been fabricated to improve the stability and delivery efficiency of the CRISPR/Cas9 system. In this context, the natural biopolymer-based carrier is a particularly promising platform for CRISPR/Cas9 delivery due to its great stability, low toxicity, excellent biocompatibility, and biodegradability. Here, the advances of natural biopolymer-based materials for CRISPR/Cas9 delivery in the cancer field are discussed.

A series of nanoparticles have been utilized for CRISPR/Cas9 delivery, including micelles, dendrimers, liposomes, SLNs, MOFs, MSNs, and AuNPs. Compared to viral vectors, nanoparticles possess favorable properties, such as low toxicity, ease of production and facile modification. Among these nanoparticles for CRISPR/Cas9 delivery, natural biopolymer-based carriers are particularly promising candidates due to their low immunogenicity, intrinsic biological activities, great stability, as well as excellent biocompatibility and biodegradability. These biopolymers can be further modified to improve their solubility and stability, DNA condensing ability, delivery efficiency, as well as stimuli-responsiveness.

The following CD-based delivery systems are mentioned:

• polyethyleneimine-β-cyclodextrin
• poly(amidoamine) dendrimer (PAMAM)/glucuronylglucosyl-β-cyclodextrin conjugate-based carrier
• adamantane-functionalized M₁₂L₂₄ metal-organic cages (Ada-MOC) self-assembled with β-cyclodextrin-conjugated polyethyleneimine (PEI-βCD) 
• self-assembled disulfide-bridged biguanidyl adamantine (Ad−SS−GD) and β−cyclodextrin-conjugated low-molecular-weight polyethyleneimine (CP) 

Lin, M.; Wang, X. Natural Biopolymer-Based Delivery of CRISPR/Cas9 for Cancer Treatment. Pharmaceutics 2024, 16, 62. https://doi.org/10.3390/pharmaceutics16010062