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.

One of the main bottlenecks in the translation of nanomedicines from research to clinics is the difficulty in designing nanoparticles actively vectorized to the target tissue, a key parameter to ensure efficacy and safety. In this group, a library of poly(beta aminoester) polymers is developed, and it is demonstrated that adding specific combinations of terminal oligopeptides (OM‐PBAE), in vitro transfection is cell selective. The current study aims to actively direct the nanoparticles to the liver by the addition of a targeting molecule. To achieve this objective, retinol, successfully attached to OM‐PBAE, is selected as hepatic targeting moiety. It is demonstrated that organ biodistribution is tailored, achieving the desired liver accumulation. Regarding cell type transfection, antigen presenting cells in the liver are those showing the highest transfection. Thanks to proteomics studies, organ but not cellular biodistribution can be explained by the formation of differential protein coronas. Therefore, organ biodistribution is governed by differential protein corona formed when retinol is present, while cellular biodistribution is controlled by the end oligopeptides type. In summary, this work is a proof of concept that demonstrates the versatility of these OM‐PBAE nanoparticles, in terms of the modification of the biodistribution of OM‐PBAE nanoparticles adding active targeting moieties.

Glioblastoma multiforme (GBM) is the most devastating primary brain tumor due to its infiltrating and diffuse growth characteristics, a situation compounded by the lack of effective treatments. Currently, many efforts are being devoted to find novel formulations to treat this disease, specifically in the nanomedicine field. However, due to the lack of comprehensive characterization that leads to insufficient data on reproducibility, only a reduced number of nanomedicines have reached clinical phases. In this context, the aim of the present study was to use a cascade of assays that evaluate from physical-chemical and structural properties to biological characteristics, both in vitro and in vivo, and also to check the performance of nanoparticles for glioma therapy. An amphiphilic block copolymer, composed of polyester and poly(ethylene glycol; PEG) blocks, has been synthesized. Using a mixture of this copolymer and a polymer containing an active targeting moiety to the Blood Brain Barrier (BBB; Seq12 peptide), biocompatible and biodegradable polymeric nanoparticles have been prepared and extensively characterized. In vitro studies demonstrated that nanoparticles are safe for normal cells but cytotoxic for cancer cells. In vivo studies in mice demonstrated the ability of the Seq12 peptide to cross the BBB. Finally, in vivo efficacy studies using a human tumor model in SCID mice resulted in a significant 50% life-span increase, as compared with non-treated animals. Altogether, this assay cascade provided extensive pre-clinical characterization of our polymeric nanoparticles, now ready for clinical evaluation.

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