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Functionalized chitosan as nano-delivery platform for CRISPR-Cas9 in cancer treatment
Asif Nawaz1, Nur Syamimi Ariffin2, Tin Wui Wong3,4,5
1Advanced Drug Delivery Laboratory, Gomal Centre of Pharmaceutical Sciences, Faculty of Pharmacy, Gomal University, DIKhan 29050, Pakistan.
Abstract:
CRISPR-Cas system permanently deletes any harmful gene-of-interest to combat cancer growth. Chitosan (CS) is a potential cancer therapeutic that mediates via PI3K/Akt/mTOR, MAPK and NF-kβ signaling pathway modulation. CS and its covalent derivatives have been designed as nanocarrier of CRISPR-Cas9 alone (plasmid or ribonucleoprotein) or in combination with chemical drug for cancer treatment. The nanocarrier was functionalized with polyethylene glycol (PEG), targeting ligand, cell penetrating ligand and its inherent positive zeta potential to mitigate premature clearance and particulate aggregation, and promote cancer cell/nucleus targeting and permeabilization to enable CRISPR-Cas9 acting on the host DNA. Different physicochemical attributes are required for the CS-based nanocarrier to survive from the administration site, through the systemic circulation-extracellular matrix-mucus-mucosa axis, to the nucleus target. CRISPR-Cas9 delivery is met with heterogeneous uptake by the cancer cells. Choice of excipients such as targeting ligand and PEG may be inappropriate due to lacking overexpressed cancer receptor or availability of excessive metabolizing enzyme and immunoglobulin that defies the survival and action of these excipients rendering nanocarrier fails to reach the target site. Cancer omics analysis should be implied to select excipients which meet the pathophysiological needs, and chitosan nanocarrier with a "transformative physicochemical behavior" is essential to succeed CRISPR-Cas9 delivery.
Insights
Chitosan nanocarriers deliver CRISPR-Cas9 gene editing tools to combat cancer. Tailoring nanocarrier properties is crucial for effective gene deletion and cancer therapy.
Area of Science:
- Biotechnology
- Nanomedicine
- Cancer Therapeutics
Background:
- CRISPR-Cas systems offer permanent gene deletion for cancer treatment.
- Chitosan (CS) and its derivatives are explored as nanocarriers for cancer therapeutics, modulating key signaling pathways.
- CS nanocarriers can be functionalized for enhanced drug delivery and targeting.
Purpose of the Study:
- To investigate the design and requirements of chitosan-based nanocarriers for effective CRISPR-Cas9 delivery in cancer treatment.
- To highlight the importance of physicochemical attributes for nanocarrier survival and function.
- To emphasize the need for cancer omics analysis in selecting appropriate nanocarrier excipients.
Main Methods:
- Designing chitosan nanocarriers functionalized with polyethylene glycol (PEG), targeting, and cell-penetrating ligands.
- Investigating the physicochemical properties required for nanocarrier traversal through biological barriers.
- Utilizing cancer omics analysis to guide excipient selection for optimal targeting and efficacy.
Main Results:
- Chitosan nanocarriers show potential for delivering CRISPR-Cas9 gene editing systems.
- Nanocarrier functionalization is critical for evading clearance and targeting cancer cells/nuclei.
- Heterogeneous cancer cell uptake and excipient interactions pose challenges to CRISPR-Cas9 delivery efficacy.
Conclusions:
- Chitosan nanocarriers require specific "transformative physicochemical behavior" for successful CRISPR-Cas9 delivery.
- Optimizing nanocarrier design based on cancer pathophysiology and omics data is essential.
- Effective delivery of CRISPR-Cas9 via nanocarriers holds promise for novel cancer therapies.
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