How to achieve target delivery of mRNA drugs to organs, cells, and tumors?-PI

In a short period of time, mRNA as a unique pharmaceutical technology has produced advancements in the fields of infectious disease and oncology therapy. One of the most difficult challenges facing mRNA therapy in the clinic today is determining how to transport mRNA to specific target cells while preventing degradation, therefore the ideal delivery vehicle must be safe, stable, and organ-specific.

Since RNA was first discovered, researchers have used diverse methods to deliver it into cells. The initial technique was naked RNA, which is susceptible to degradation by RNase and causes a strong pro-inflammatory response. Later formulations developed for RNA delivery are carbohydrate polymers, polyethylenimine (PEI), etc. Due to its positive charge and abundant amines, PEI has good affinity for nucleic acids, resulting in complexes with positive surface charges. In vivo, PEIs have been successfully used for aerosol gene delivery to the lung. Despite the high transfection efficiency of PEI preparations in vitro and in vivo, they are also significantly cytotoxic, partly due to their poor degradability, preventing the wider use of PEI-based vectors in preclinical and clinical settings.

Polyester is another type of material utilized for RNA delivery, and adding pluripotent F127 lowers the nanoparticles' overall charge and enhances their stability. Manipulation of F127 content results in the delivery of lung-specific mRNA, which can be exploited to treat lung diseases.

Local drug EluteR (LODERTM), a tiny biodegradable polymeric substrate, was created for extended siRNA delivery to pancreatic tumors and tested in a phase 1/2a clinical trial in combination with chemotherapy.

Natural chitosan is a biodegradable, biocompatible, and cationically charged carbohydrate polymer that allows nucleic acid binding. However, it has drawbacks such as poor water solubility and limited targeting ability.

Lipid nanoparticles (LNPs) are the most common RNA therapeutic vectors in use today. Lipids are water-insoluble organic lipid molecules with hydrophilic heads and hydrophobic tails that allow LNPs to self-assemble into well-defined structures like cell membranes. Hydrophobic interactions in the aqueous environment, as well as negatively charged RNA and cationic or ionizable RNA, combine to produce LNP-RNA complexes. Electrostatic interactions between negatively charged RNA and cationic or ionizable lipids in an aqueous environment generate the LNP-RNA system. Ionizable lipids are positively charged at low pH (allowing RNA binding) and neutral at physiological pH, reducing the toxicity of LNP-RNA complexes in vivo.

Organ Targeted Delivery

How can intramuscular LNP-RNA be precisely delivered to target organs for systemic immunization? Apolipoprotein E (ApoE) in the blood attaches to LNPs administered intravenously, and the liver is the organ responsible for eliminating ApoE-bound lipoproteins. As a result, systemically given LNP-RNA will bind ApoE and reach the liver preferentially. A significant disadvantage of intravenously injected ionizable LNPs is excessive liver homing, which can be mitigated via a selective organ targeting (SORT) technique.

Manipulation of the internal and/or external charge of the formed LNPs is key to organ-specific delivery.

The addition of SORT molecules to the typical LNP components of ionizable cationic lipids, phospholipids, cholesterol, and PEG results in gene transport to the lungs, spleen, and liver. Tissue tropism moves from the liver to the lung when the percentage of continuously positively charged DDAB and EPC increases. Spleen-specific distribution is achieved by increasing the negatively charged 1,2-dienoyl-sn-glycero-3-phosphate (14PA) SORT molecule by 10-40%. Hepatic targeting is also improved by using the right ratio of DODAP and C12-200.

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