Scope and challenges of nanoparticle-based mRNA delivery in cancer treatment

Abstract

Messenger RNA (mRNA) recently emerged as an appealing alternative to treat and prevent diseases ranging from cancer and Alzheimer’s disease to COVID-19 with significant clinical outputs. The in vitro-transcribed mRNA has been engineered to mimic the structure of natural mRNA for vaccination, cancer immunotherapy and protein replacement therapy. In past decades, significant progress has been noticed in unveiling the molecular pathways of mRNA, controlling its translatability and stability, and its evolutionary defense mechanism. However, numerous unsolved structural, biological, and technical difficulties hamper the successful implementation of systemic delivery of mRNA for safer human consumption. Advances in designing and manufacturing mRNA and selecting innovative delivery vehicles are mandatory to address the unresolved issues and achieve the full potential of mRNA drugs. Despite the substantial efforts made to improve the intracellular delivery of mRNA drugs, challenges associated with diverse applications in different routes still exist. This study examines the current progress of mRNA therapeutics and advancements in designing biomaterials and delivery strategies, the existing translational challenges of clinical tractability and the prospects of overcoming any challenges related to mRNA.

Prolonged Circulation and Enhanced Tumor Uptake of PEGylated Nanoparticles by Manipulation of Nanoscale Surface Topography

“…36 In particular, emerging applications such as nucleic acid therapies rely on more advanced delivery strategies to achieve sufficient uptake of therapeutics into target cells. 40,41 Here, we observed extraordinarily high uptake of rough nanoparticles into tumor cells with close to 70% nanoparticle-positive cells after 48 hours compared to ~5% for conventional smooth PLA-PEG nanoparticles (Figure 5a). The uptake remained high for Di-5k and Tri-5k (~50% positive cells) even after 7 days but was significantly reduced for Di-2k and Tri-2k (less than 20%) (Figure 5b) possibly due to their differences in surface topography (e.g.…”

Biodrug Delivery Systems: Do mRNA Lipid Nanoparticles Come of Age?

“…However, numerous unsolved structural, biological, and technical difficulties hamper the successful implementation of the systemic delivery of mRNA for safe human consumption. Advances in designing and manufacturing mRNA and selecting innovative delivery vehicles are mandatory to address the unresolved issues and achieve the full potential of mRNA drugs [43].…”

Design and fabrication of intracellular therapeutic cargo delivery systems based on nanomaterials: current status and future perspectives

“…72 The main components of LNPs are mostly ionized cationic lipids or cationic lipoid compounds, etc. 73 It shows many advantages over liposomes in terms of high nucleic acid encapsulation rate as well as high tissue penetration. 74,75 More specifically, this is because the positive charge of liposomes can conjugate to phosphate groups in nucleic acid molecules through electrostatic interactions, forming complexes that allow easier passage of nucleic acids through the cell membrane.…”

“…Furthermore, when LNPs enter the intracellular endosomes, the amine groups of ionizable cationic lipids protonate and bind to the anionic groups on the endosomal membrane, thus contributing to the escape of nucleic acids from the endosomes. 73,75 In terms of protein delivery, LNPs need to be customized for each protein to be delivered, owing to complex and various structures of proteins. Notably, increasing negative charge density of proteins, thus allowing them to bind to cationic lipids, is critical for efficient encapsulation capability and adequate product stability in clinical translation.…”