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ARC is a prevalent condition in critically ill patients, especially in young people, with urinary CrCl being the best diagnostic method because mathematical estimates tend to underestimate CrCl. ARC increases renal drug elimination and has a clear influence on certain antimicrobial plasma levels, but is yet to define its impact on clinical outcomes and on pharmacokinetics of other types of drugs. Research on the need to stage ARC and establish specific dosing guidelines is warranted.

The use of messenger RNA (mRNA) in gene therapy is increasing in recent years, due to its unique features compared to plasmid DNA: Transient expression, no need to enter into the nucleus and no risk of insertional mutagenesis. Nevertheless, the clinical application of mRNA as a therapeutic tool is limited by its instability and ability to activate immune responses; hence, mRNA chemical modifications together with the design of suitable vehicles result essential. This manuscript includes a revision of the strategies employed to enhance in vitro transcribed (IVT) mRNA functionality and efficacy, including the optimization of its stability and translational efficiency, as well as the regulation of its immunostimulatory properties. An overview of the nanosystems designed to protect the mRNA and to overcome the intra and extracellular barriers for successful delivery is also included. Finally, the present and future applications of mRNA nanomedicines for immunization against infectious diseases and cancer, protein replacement, gene editing, and regenerative medicine are highlighted.

P-gp substrate 22Caco-2 23 M cell 24The aims of this work were (i) to evaluate the potential of nanostructured lipid carriers (NLCs) as a tool to 25 enhance the oral bioavailability of poorly soluble compounds using saquinavir (SQV), a BCS class IV drug 26 and P-gp substrate as a model drug, and (ii) to study NLC transport mechanisms across the intestinal barrier.27 Three different NLC formulations were evaluated. SQV transport across Caco-2 monolayers was enhanced up 28 to 3.5-fold by NLCs compared to SQV suspension. M cells did not enhance the transport of NLCs loaded with 29 SQV. The size and amount of surfactant in the NLCs influenced SQV's permeability, the transcytosis pathway 30 and the efflux of SQV by P-gp. An NLC of size 247 nm and 1.5% (w/v) surfactant content circumvented P-gp 31 efflux and used both caveolae-and clathrin-mediated transcytosis, in contrast to the other NLC formulations, 32 which used only caveolae-mediated transcytosis. By modifying critical physicochemical parameters of the 33 NLC formulation, we were thus able to overcome the P-gp drug efflux and alter the transcytosis mechanism 34 of the nanoparticles. These findings support the use of NLCs approaches for oral delivery of poorly 35 water-soluble P-gp substrates.36

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