Oligonucleotide-Based Therapeutics for STAT3 Targeting in Cancer-Drug Carriers Matter

Simple Summary Activated STAT3 is an essential factor in cancer development; therefore, blocking STAT3 may be of therapeutic benefit in multiple cancer types. Thanks to recent developments in the regulatory function of non-coding nucleic acids, a new branch of nucleic acid-based molecules with significant therapeutic potential has emerged. Therapeutics such as siRNA, shRNA, ASO, and ODN-decoy that target STAT3 found an application in cancer therapies. The main advantage of using nucleic acid-based therapeutics is their high specificity based on the complementarity of the therapeutic sequence with the target. Conversely, oligonucleotide therapeutics struggle with stability, toxicity, sensitivity to nucleases, specificity toward cell type, and cellular uptake, which hamper their applicability. Among the various solutions proposed to overcome these problems, embedding the oligonucleotide in the carrier is an interesting strategy. The review combines the knowledge about STAT3 biology in cancer, the application of anti-STAT3 oligonucleotide therapeutics in cancer therapy, and carriers for their delivery.Abstract High expression and phosphorylation of signal transducer and transcription activator 3 (STAT3) are correlated with progression and poor prognosis in various types of cancer. The constitutive activation of STAT3 in cancer affects processes such as cell proliferation, apoptosis, metastasis, angiogenesis, and drug resistance. The importance of STAT3 in cancer makes it a potential therapeutic target. Various methods of directly and indirectly blocking STAT3 activity at different steps of the STAT3 pathway have been investigated. However, the outcome has been limited, mainly by the number of upstream proteins that can reactivate STAT3 or the relatively low specificity of the inhibitors. A new branch of molecules with significant therapeutic potential has emerged thanks to recent developments in the regulatory function of non-coding nucleic acids. Oligonucleotide-based therapeutics can silence target transcripts or edit genes, leading to the modification of gene expression profiles, causing cell death or restoring cell function. Moreover, they can reach untreatable targets, such as transcription factors. This review briefly describes oligonucleotide-based therapeutics that found application to target STAT3 activity in cancer. Additionally, this review comprehensively summarizes how the inhibition of STAT3 activity by nucleic acid-based therapeutics such as siRNA, shRNA, ASO, and ODN-decoy affected the therapy of different types of cancer in preclinical and clinical studies. Moreover, due to some limitations of oligonucleotide-based therapeutics, the importance of carriers that can deliver nucleic acid molecules to affect the STAT3 in cancer cells and cells of the tumor microenvironment (TME) was pointed out. Combining a high specificity of oligonucleotide-based therapeutics toward their targets and functionalized nanoparticles toward cell type can generate very efficient formulations.