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upregulation of stress-response genes, downregulation of proliferation-associated genes, and reduced levels
of several apoptosis- and glycolysis-related proteins [146,147] . Another instance of an off-target effect is the
[148]
termination of the anti-miR-122 therapeutic RG-101 due to elevated levels of bilirubin in the blood .

Delivery methods
The efficient delivery of RNA therapeutics, ensuring they reach the intended organ and cell type and
successfully traverse the cell membrane to exert their intracellular functions, remains a formidable challenge
in the field. Various strategies address the formulation of RNA therapeutics and their delivery mechanisms.
Nucleotide modifications play a role in enhancing stability by evading nucleases and reducing interactions
with proteins. Delivery mechanisms encompass lipid nanoparticles, polymers like polyethylene imine,
polylactic-co-glycolic acid, poly-amidoamine, and chitosan. Additionally, conjugation to active molecules,
such as N-acetylgalactosamine, is employed to enhance delivery efficiency .
[106]

Toxicity
Toxicity is another crucial consideration in the administration of RNA therapeutics. For instance, it has
been demonstrated that off-target effects are more sensitive to small concentrations of siRNAs than on-
target silencing . Many RNA therapeutics leverage endogenous RNA interference machinery, and
[149]
excessive dosing can lead to system saturation, impeding the function of endogenous microRNAs. The
initial report of this phenomenon indicated that robust shRNA overexpression in hepatocytes resulted in a
global downregulation of microRNAs, leading to liver toxicity and mortality in mice . A comprehensive
[150]
screening study confirmed that the global upregulation of microRNA target genes is a general occurrence
triggered by the introduction of exogenous small RNAs .
[151]

Undesired on-target effects can contribute to the toxicity of RNA therapeutics. For example, in the case of
MRX34, it was observed that the therapeutic was taken up by white blood cells . Since miR-34a plays a
[143]
significant role in T cells and macrophages, incubation with a miR-34a mimic led to changes in chemokine
[152]
profiles in macrophages and T cells . This is believed to be a factor in the low response rate and adverse
[106]
immune effects observed in the clinical trial of MRX34 . Similarly, the increased chemotherapy-induced
neuropathy in patients receiving the AEG35156 ASO may be attributed to the downregulation of the XIAP
gene not only in tumor cells but also in oligodendrocytes, glial cells, or neuronal cells, leading to these
[153]
undesirable effects .

CONCLUDING REMARKS
LncRNAs are a class of RNA transcripts that are long (i.e., more than 200 nucleotides) and not translated
into proteins . LncRNAs vary considerably in function and play critical roles in many pathophysiological
[6]
processes, such as RNA splicing and X-chromosome inactivation [1,10] . LncRNAs often exhibit low expression
levels and are typically associated with specific tissues or cell types . They have been growing as new
[7]
[8]
contributors to cancer in both oncogenic and tumor suppressive pathways . Being involved in various
physiological functions, lncRNAs can be involved in pathology and the potential treatment of different
diseases.

LncRNAs have shown their involvement as either pathological markers and/or therapeutic potential targets
in diseases such as brain injury [52-54] , spinal cord injury [14,59-61] , Alzheimer’s disease [65-67] , Huntington’s
disease [76,77] , prostate cancer [79,80] , breast cancer [83,84] , and many other diseases [154-158] . Recently, researchers have
begun to target RNAs as potential drug targets or formulate RNA-based drugs for which they offer greater
specificity and stability than proteins . Different RNA-based drugs include antisense oligonucleotides ,
[14]
[106]
microRNA mimics , anti-microRNAs , microRNA sponges , microRNA masks , small interfering
[106]
[111]
[117]
[112]