Targeting lncRNAs to Overcome Cancer Therapy Resistance: Advances in RNA Therapeutics and Delivery Strategies

Non-coding RNAs (ncRNAs) are increasingly recognized as important regulators of cancer biology. Long non-coding RNAs (lncRNAs), defined as transcripts longer than 200 nucleotides, gain particular attention due to their cancer-specific expression patterns and functional roles in tumor progression, metastasis and therapeutic resistance. Although lncRNAs have been extensively studied as diagnostic, prognostic and predictive biomarkers, growing evidence indicates that they can also act as active mediators of therapeutic resistance, supporting their potential as therapeutic candidates. Here, we summarize how lncRNAs contribute to resistance against radiotherapy, chemotherapy, immunotherapy and targeted therapy, highlighting their molecular mechanisms. Next, we discuss RNA-based therapeutics as a strategy to target disease-relevant transcripts, focusing on antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), microRNA (miRNA) mimics and antimiRs, as well as approved RNA therapeutic agents, oncology-focused candidates in clinical development and emerging preclinical approaches directed against lncRNAs or lncRNA-controlled regulatory axes. Finally, we examine delivery platforms, including lipid-based nanovectors, extracellular vesicles, polymeric systems and other approaches designed to overcome key translational barriers, such as RNA instability, off-target effects, immune activation, renal clearance and inefficient tumor-specific delivery. By connecting lncRNA-mediated resistance mechanisms with RNA therapeutic strategies and delivery technologies, this review highlights lncRNA-directed RNA therapeutics as a promising yet developing approach in oncology.