mRNA Delivery System for Targeting Antigen‐Presenting Cells In Vivo

Abstract

The encapsulation of mRNA in nanosystems as gene vaccines for immunotherapy purposes has experienced an exponential increase in recent years. Despite the many advantages envisaged within these approaches, their application in clinical treatments is still limited due to safety issues. These issues can be attributed, in part, to liver accumulation of most of the designed nanosystems and to the inability to transfect immune cells after an intravenous administration. In this context, this study takes advantage of the known versatile properties of the oligopeptide end-modified poly (β-amino esters) (OM-PBAEs) to complex mRNA and form discrete nanoparticles. Importantly, it is demonstrated that the selection of the appropriate end-oligopeptide modifications enables the specific targeting and major transfection of antigen-presenting cells (APC) in vivo, after intravenous administration, thus enabling their use for immunotherapy strategies. Therefore, with this study, it can be confirmed that OM-PBAE are appropriate systems for the design of mRNA-based immunotherapy approaches aimed to in vivo transfect APCs and trigger immune responses to fight either tumors or infectious diseases.

Synthesis and mechanistic investigations of pH-responsive cationic poly(aminoester)s

“…[23][24][25]30,33 Cationic poly(b-aminoester)s have demonstrated good biocompatibility and are used in a wide range of biomedical applications, 34,35 highlighted by recent advances in gene delivery vehicles for a variety of therapeutic indications. [36][37][38][39][40][41][42][43] We recently reported a novel class of materials based on cationic poly(a-aminoester) backbones that undergo a pHsensitive rapid and selective degradation to neutral amide and amino acid byproducts in water. 44 We have leveraged this behavior in the design of novel cationic amphiphilic oligomers, charge-altering releasable transporters (CARTs), 33,[45][46][47] that bind, complex, and deliver oligonucleotides of wide ranging size (mRNA, pDNA) into cells, in vitro and in vivo.…”

Tracking the DNA complexation state of pBAE polyplexes in cells with super resolution microscopy

“…30,31 Recently, we have developed a new family of oligopeptide terminated poly(β-amino ester)s that are able to form polyplexes with different kinds of oligonucleotides and are able to efficiently transfect them both in vitro and in vivo. 26,[32][33][34][35] With a combination of dSTORM microscopy and single molecule image analysis tools, we were able to quantify their stability and DNA release during cell uptake, trafficking and nuclear entry, i.e. the main barriers towards successful transfection.…”

In Vivo Retargeting of Poly(beta aminoester) (OM‐PBAE) Nanoparticles is Influenced by Protein Corona

“…This polymer family is appropriate for biomedical applications thanks to their biocompatibility, biodegradability, and buffering capacity, useful to escape from the endosome after endocytosis, thus enabling nucleic acid expression inside cells. In addition, OM‐PBAEs are able to self‐ensemble in the presence of anionic gene material in discrete small nanometric polyplexes (or nanoparticles) . In our previous publication, we demonstrated that we can perform a cell‐type selective transfection not only in vitro, but also in vivo, after intravenous administration.…”

“…In addition, OM‐PBAEs are able to self‐ensemble in the presence of anionic gene material in discrete small nanometric polyplexes (or nanoparticles) . In our previous publication, we demonstrated that we can perform a cell‐type selective transfection not only in vitro, but also in vivo, after intravenous administration. Moreover, selecting the appropriate end‐oligopeptide terminated polymer combination, which could be considered an indirect targeting strategy, we were able to promote the preferential accumulation and transfection of selected OM‐PBAE nanoparticles in the spleen; i.e., we avoided the unspecific liver accumulation that is usually a problem for many nanosystems.…”

“…Therefore, finding novel delivery systems actively targeted to liver diseased cells would represent a step forward in improving a huge variety of patients' quality of life. The versatility and robustness of our OM‐PBAE nanoparticles to complex many different types of gene material, codifying for different genes, makes them promising carriers for any liver disease requiring a gene, and consequently protein expression modification. For this reason, in this work, we pursued the redirection of our nanoparticles to the liver using an active homing device.…”