RNA drugs and nonviral nanocarriers in oncology - present status and emerging concepts.

RNA molecules offer attractive therapeutic strategies in oncology, based on mechanisms of action different to existing medications. The therapeutic application of RNAs, however, is still associated with major bottlenecks, including poor stability and pharmacokinetics. Non-viral nanoparticle formulations represent systems for RNA protection, delivery and cell internalization. They have to meet defined requirements for providing sufficient efficacy, specificity and biocompatibility. Moreover, the selection of the RNA drug as payload is of major relevance. As a result of intense research over the past decades, a wide variety of different RNA classes are available for interference with pathophysiological processes. This review provides an overview of various RNA classes as drug candidates, including RNAs mediating loss-of-function (siRNAs for gene knockdown, sgRNAs for gene knockout, gene- or base-editing), gain-of-function (mRNA, sa-mRNA, circRNA for ectopic overexpression) or modulation of gene expression (miRNAs, antimiRs or circRNAs for miRNA inhibition), among others. Dependent on the target organ, target cell and type of RNA molecule, different nanoparticle systems can provide efficient RNA formulations. New therapeutic strategies may also cover combinations of different types of RNAs, associated with different properties and thus requiring even more sophisticated nanocarriers for their delivery. The various classes of nanocarriers available for RNA formulation are reviewed and discussed as well. Beyond therapeutic in vivo application, RNA-based strategies may also be of relevance in cell-based therapies, for non-viral ex vivo modification of immune cells. While this would offer advantages over existing viral transduction strategies, it will also rely on sufficiently efficient non-viral systems for cell modification. Overall, nonviral systems for the delivery of RNA therapeutics are needed to fulfil the potential of these approaches in the clinic.