Noncoding RNA (ncRNA) therapeutics, including microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), offer promising approaches for treating cancers and other diseases. However, clinical trials have shown mixed results, with some studies reporting potent effects and others demonstrating limited efficacy or toxicity. Alternative entities like antimirRNAs and lncRNA-based therapeutics are gaining interest. Key challenges include specificity, delivery, and tolerability, with emerging approaches aiming to improve success rates. ncRNAs are noncoding transcripts that regulate gene expression and protein function. miRNAs are small, 17-25 nucleotide molecules that regulate gene expression, while lncRNAs are larger transcripts that interact with DNA, RNA, and proteins. Both types of ncRNAs have been linked to cancer and other diseases. Various RNA-based therapies, including antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), and miRNA mimics, have been developed, with several FDA-approved. However, many RNA-based therapeutics face challenges in clinical translation due to issues with specificity, delivery, and immune responses. Immune responses are a major hurdle, as RNA can activate toll-like receptors (TLRs), leading to adverse effects. Chemical modifications, such as 2'-O-methyl and locked nucleic acids (LNAs), are used to reduce immunogenicity. Metronomic RNA therapy, involving regular low-dose administration, is being explored to minimize toxicity and immune responses. Combinatorial therapies, using RNA therapeutics in conjunction with other treatments, may enhance efficacy and reduce side effects. Potential solutions include expanding immune-related adverse reaction screening, using 'tiny' antisense RNAs, and developing nanoparticles for co-delivery of multiple therapeutics. Small-molecule inhibitors of miRNAs are also being explored as alternatives to RNA-based therapies. Despite these advancements, challenges remain in ensuring specificity, potency, and safety for clinical application. Targeting ncRNAs with interaction element blockers and structural element lockers is a new approach that may improve therapeutic outcomes. Overall, while RNA-based therapeutics show promise, overcoming challenges related to specificity, delivery, and immune responses is crucial for their successful clinical application.Noncoding RNA (ncRNA) therapeutics, including microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), offer promising approaches for treating cancers and other diseases. However, clinical trials have shown mixed results, with some studies reporting potent effects and others demonstrating limited efficacy or toxicity. Alternative entities like antimirRNAs and lncRNA-based therapeutics are gaining interest. Key challenges include specificity, delivery, and tolerability, with emerging approaches aiming to improve success rates. ncRNAs are noncoding transcripts that regulate gene expression and protein function. miRNAs are small, 17-25 nucleotide molecules that regulate gene expression, while lncRNAs are larger transcripts that interact with DNA, RNA, and proteins. Both types of ncRNAs have been linked to cancer and other diseases. Various RNA-based therapies, including antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), and miRNA mimics, have been developed, with several FDA-approved. However, many RNA-based therapeutics face challenges in clinical translation due to issues with specificity, delivery, and immune responses. Immune responses are a major hurdle, as RNA can activate toll-like receptors (TLRs), leading to adverse effects. Chemical modifications, such as 2'-O-methyl and locked nucleic acids (LNAs), are used to reduce immunogenicity. Metronomic RNA therapy, involving regular low-dose administration, is being explored to minimize toxicity and immune responses. Combinatorial therapies, using RNA therapeutics in conjunction with other treatments, may enhance efficacy and reduce side effects. Potential solutions include expanding immune-related adverse reaction screening, using 'tiny' antisense RNAs, and developing nanoparticles for co-delivery of multiple therapeutics. Small-molecule inhibitors of miRNAs are also being explored as alternatives to RNA-based therapies. Despite these advancements, challenges remain in ensuring specificity, potency, and safety for clinical application. Targeting ncRNAs with interaction element blockers and structural element lockers is a new approach that may improve therapeutic outcomes. Overall, while RNA-based therapeutics show promise, overcoming challenges related to specificity, delivery, and immune responses is crucial for their successful clinical application.