Conformation-sensitive targeting of lipid nanoparticles for RNA therapeutics.

The successful in vivo implementation of gene expression modulation strategies relies on effective, non-immunogenic delivery vehicles. Lipid nanoparticles are one of the most advanced non-viral clinically approved nucleic-acid delivery systems. Yet lipid nanoparticles accumulate naturally in liver cells upon intravenous administration, and hence, there is an urgent need to enhance uptake by other cell types.

Design of SARS-CoV-2 hFc-Conjugated Receptor-Binding Domain mRNA Vaccine Delivered Lipid Nanoparticles.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been identified as the causal agent of COVID-19 and stands at the center of the current global human pandemic, with death toll exceeding one million. The urgent need for a vaccine has led to the development of various immunization approaches. mRNA vaccines represent a cell-free, simple, and rapid platform for immunization, and therefore have been employed in recent studies toward the development of a SARS-CoV-2 vaccine.

Paving the Road for RNA Therapeutics.

Therapeutic RNA molecules possess high potential for treating medical conditions if they can successfully reach the target cell upon administration. However, unmodified RNA molecules are rapidly degraded and cleared from the circulation. In addition, their large size and negative charge complicates their passing through the cell membrane.

Progress and challenges towards CRISPR/Cas clinical translation.

CRISPR/Cas systems (clustered regularly interspaced short palindromic repeats) have emerged as powerful tools to manipulate the genome for both research and therapeutic purposes. However, the clinical use of this system is hindered by multiple challenges, such as the rate of off-target effects, editing efficiency, the efficacy of HDR, immunogenicity, as well as development of efficient and safe delivery vehicles that can carry these compounds. Tremendous efforts are being conducted to overcome these challenges, including the discovery and engineering of more precise and efficacious Cas nucleases.

A Combinatorial Library of Lipid Nanoparticles for RNA Delivery to Leukocytes.

Lipid nanoparticles (LNPs) are the most advanced nonviral platforms for small interfering RNA (siRNA) delivery that are clinically approved. These LNPs, based on ionizable lipids, are found in the liver and are now gaining much attention in the field of RNA therapeutics. The previous generation of ionizable lipids varies in linker moieties, which greatly influences in vivo gene silencing efficiency.

Monoclonal antibody-based molecular imaging strategies and theranostic opportunities.

Molecular imaging modalities hold great potential as less invasive techniques for diagnosis and management of various diseases. Molecular imaging combines imaging agents with targeting moieties to specifically image diseased sites in the body. Monoclonal antibodies (mAbs) have become increasingly popular as novel therapeutics against a variety of diseases due to their specificity, affinity and serum stability.

Therapeutic mRNA delivery to leukocytes.

In the past few years mRNA molecules have become an attractive class of new drugs with numerous opportunities. mRNA therapeutics holds great potential for the treatment of a variety of diseases and is an emerging field both in academia and in the pharma industry. Among the various mRNA-based therapeutic approaches, immunotherapy is one of the pioneering and most advanced therapy to date.

Cell specific delivery of modified mRNA expressing therapeutic proteins to leukocytes.

Therapeutic alteration of gene expression in vivo can be achieved by delivering nucleic acids (e.g., mRNA, siRNA) using nanoparticles.

A modular platform for targeted RNAi therapeutics.

Previous studies have identified relevant genes and signalling pathways that are hampered in human disorders as potential candidates for therapeutics. Developing nucleic acid-based tools to manipulate gene expression, such as short interfering RNAs (siRNAs), opens up opportunities for personalized medicine. Yet, although major progress has been made in developing siRNA targeted delivery carriers, mainly by utilizing monoclonal antibodies (mAbs) for targeting, their clinical translation has not occurred.

Current Progress in Non-viral RNAi-Based Delivery Strategies to Lymphocytes.

RNAi-based therapy holds great promise, as it can be utilized for the treatment of multiple conditions in an accurate manner via sequence-specific manipulation of gene expression. To date, RNAi therapeutics have advanced into clinical trials for liver diseases and solid tumors; however, delivery of RNAi to leukocytes in general and to lymphocytes in particular remains a challenge. Lymphocytes are notoriously hard to transduce with RNAi payloads and are disseminated throughout the body, often located in deep tissues; therefore, developing an efficient systemic delivery system directed to lymphocytes is not a trivial task.