Advances in non-viral mRNA delivery to the spleen.

Developing safe and effective delivery strategies for localizing messenger RNA (mRNA) payloads to the spleen is an important goal in the field of genetic medicine. Accomplishing this goal is challenging due to the instability, size, and charge of mRNA payloads. Here, we provide an analysis of non-viral delivery technologies that have been developed to deliver mRNA payloads to the spleen. Specifically, our review begins by outlining the unique anatomy and potential targets for mRNA delivery within the spleen. Next, we describe approaches in mRNA sequence engineering that can be used to improve mRNA delivery to the spleen. Then, we describe advances in non-viral carrier systems that can package and deliver mRNA payloads to the spleen, highlighting key advances in the literature in lipid nanoparticle (LNP) and polymer nanoparticle (PNP) technology platforms. Finally, we provide commentary and outlook on how splenic mRNA delivery may afford next-generation treatments for autoimmune disorders and cancers. In undertaking this approach, our goal with this review is to both establish a fundamental understanding of drug delivery challenges associated with localizing mRNA payloads to the spleen, while also broadly highlighting the potential to use these genetic medicines to treat disease.

Polyphenolic Nanoparticle Platforms (PARCELs) for In Vitro and In Vivo mRNA Delivery.

Despite their successful implementation in the COVID-19 vaccines, lipid nanoparticles (LNPs) still face a central limitation in the delivery of mRNA payloads: endosomal trapping. Improving upon this inefficiency could afford improved drug delivery systems, paving the way toward safer and more effective mRNA-based medicines. Here, we present polyphenolic nanoparticle platforms (PARCELs) as effective mRNA delivery systems. In brief, our investigation begins with a computationally guided structural analysis of 1825 discrete polyphenolic structural data points across 73 diverse small molecule polyphenols and 25 molecular parameters. We then generate structurally diverse PARCELs, evaluating their in vitro mechanism and activity, ultimately highlighting the superior endosomal escape properties of PARCELs relative to analogous LNPs. Finally, we examine the in vivo biodistribution, protein expression, and therapeutic efficacy of PARCELs in mice. In undertaking this approach, the goal of this study is to establish PARCELs as viable delivery platforms for safe and effective mRNA delivery.

Engineering nanoparticle toolkits for mRNA delivery.

The concept of using mRNA to produce its own medicine in situ in the body makes it an ideal drug candidate, holding great potential to revolutionize the way we approach medicine. The unique characteristics of mRNA, as well as its customizable biomedical functions, call for the rational design of delivery systems to protect and transport mRNA molecules. In this review, a nanoparticle toolkit is presented for the development of mRNA-based therapeutics from a drug delivery perspective. Nano-delivery systems derived from either natural systems or chemical synthesis, in the nature of organic or inorganic materials, are summarised. Delivery strategies in controlling the tissue targeting and mRNA release, as well as the role of nanoparticles in building and boosting the activity of mRNA drugs, have also been introduced. In the end, our insights into the clinical and translational development of mRNA nano-drugs are presented.

Ongoing Clinical Trials of Nonviral siRNA Therapeutics.

Short interfering RNAs (siRNA) are a powerful class of genetic medicines whose clinical translation can be hindered by their suboptimal delivery properties in vivo. Here, we provide a clinically focused overview that summarizes ongoing siRNA clinical trials from the perspective of innovations in nonviral delivery strategies. More specifically, our review begins by highlighting the delivery barriers and physiochemical properties of siRNA that make it challenging to deliver it in vivo. We then provide commentary on specific delivery strategies, including sequence modification, siRNA ligand conjugation, and nanoparticle and exosomal packaging, each of which can be used to control the delivery of siRNA therapies in living systems. Last, we provide a summary table of ongoing siRNA clinical trials which also highlights the indication of use, target, and National Clinical Trial (NCT) number associated with each entry. In writing this review, our work aims to highlight the key challenges and strategies for effective nonviral siRNA delivery in vivo, while simultaneously summarizing information on ongoing clinical trials for siRNA therapy in humans.