miRNA- and lncRNA-Based Therapeutics for Non-Hodgkin’s Lymphoma: Moving towards an RNA-Guided Precision Medicine

SIMPLE SUMMARY: Non-Hodgkin’s lymphoma (NHL) is a very heterogenous class of hematological cancers, with variable patient outcomes. Therefore, there is an urgent need to develop new and more effective therapeutic approaches. MiRNAs and lncRNAs have emerged as the central gene expression regulators, and their deregulation has been reported to be involved in lymphomagenesis. Given their ability to simultaneously modulate multiple targets, they provide an attractive therapeutic approach to treat NHL patients. In this review, we discuss the scientific rationale behind miRNA/lncRNA-based therapies in NHL and the different targeting technologies, such as antisense oligonucleotides, CRISPR-Cas9, and nanomedicines. ABSTRACT: Increasing evidence has demonstrated the functional roles of miRNAs and lncRNAs in lymphoma onset and progression, either by acting as tumor-promoting ncRNAs or as tumor suppressors, emphasizing their appeal as lymphoma therapeutics. In fact, their intrinsic ability to modulate multiple dysregulated genes and/or signaling pathways makes them an attractive therapeutic approach for a multifactorial pathology like lymphoma. Currently, the clinical application of miRNA- and lncRNA-based therapies still faces obstacles regarding effective delivery systems, off-target effects, and safety, which can be minimized with the appropriate chemical modifications and the development of tumor site-specific delivery approaches. Moreover, miRNA- and lncRNA-based therapeutics are being studied not only as monotherapies but also as complements of standard treatment regimens to provide a synergic effect, improving the overall treatment efficacy and reducing the therapeutic resistance. In this review, we summarize the fundamentals of miRNA- and lncRNA-based therapeutics by discussing the different types of delivery systems, with a focus on those that have been investigated in lymphoma in vitro and in vivo. Moreover, we described the ongoing clinical trials of novel miRNA- and lncRNA-based therapeutics in lymphoma.