Nanomaterial-Mediated Nucleic Acid Delivery for Pancreatic Cancer Therapeutics.

Pancreatic cancer (PC), one of the most aggressive and lethal malignancies, remains an imminent threat to human health despite enormous advancements in cancer research. Traditional therapeutic approaches are unable to significantly enhance the life expectancy of PC patients due to limitations such as lower targetability, recurrence of cancerous tumors, and side effects on healthy cells. Nucleic acid therapeutics (NATs) offer a promising alternative against traditional approaches due to their ability to target and modify genetic pathways involved in PC progression, thus providing precision treatment. However, their efficient transportation to cancerous cells and tissues is still a major obstacle. Because of the high biocompatibility, tunable physicochemical characteristics, surface functionalization potential, and scalable manufacturing potential, nanomaterials have established themselves as a frontrunner as a delivery carrier against different diseases. Considering this, different nanocarriers were explored as a vehicle for anticancer therapeutics, especially to deliver therapeutic drugs, NATs, etc., and also provided a shield against enzymatic and chemical degradation in the bloodstream while promoting tumor-specific accumulation and targetability. Pertaining to this, in the current review, we have systematically discussed the development of nanomaterial-based NATs delivery systems for the delivery of nucleic acids like siRNA, miRNA, mRNA, saRNA, pDNA, CRISPR-Cas9 guide RNA, and other nucleic acids against PC, with an emphasis on their benefits, drawbacks, and translational potential. We also highlighted and compared the preclinical assessment of nanomaterial-mediated NATs delivery in PC therapy in wild-type and drug-resistant PC cells and discussed NATs delivery in two-dimensional (2D) and three-dimensional (3D) cell culture models alongside in vivo and clinical studies. Additionally, we also explored the possibilities of the 3D cell culture model's advantage over traditional 2D cell cultures and their relevance to in vivo systems, especially in facilitating NATs delivery and clinical translation possibilities, and paved the way for future research and clinical applications toward precision medicine.