siRNA and miRNA are non-coding RNAs that regulate gene expression. They have been investigated as potential therapeutic agents for treating diseases such as cancer and infections. While both siRNAs and miRNAs target mRNA for gene silencing, they differ in their mechanisms of action and clinical applications. siRNAs are highly specific and target a single mRNA, whereas miRNAs have multiple targets. Therapeutic approaches for siRNAs involve RNA interference (RNAi) to inhibit mRNA expression, while miRNA-based therapies include miRNA inhibition and replacement. The review discusses the mechanisms, physicochemical properties, delivery, and clinical applications of siRNAs and miRNAs, as well as the challenges in developing them as therapeutics. siRNAs are processed by Dicer into a short dsRNA molecule, which is loaded into the RNA-induced silencing complex (RISC) to cleave target mRNA. miRNAs are processed through a similar pathway but are loaded into the miRISC complex, where they guide the complex to target mRNA for degradation or repression. siRNAs are more specific and can target a single mRNA, while miRNAs regulate multiple mRNAs. Both siRNAs and miRNAs face challenges such as poor stability, delivery issues, and off-target effects. The design of therapeutic siRNAs requires careful consideration of sequence, strand orientation, and G/C content to ensure specificity and efficiency. Off-target effects can occur due to partial complementarity with unintended targets. Strategies to reduce off-target effects include using lower concentrations of siRNAs, pooling multiple siRNAs targeting the same mRNA, and avoiding complementarity with the seed region of mRNA. Chemical modifications such as 2'-O-methyl, 2'-fluoro, and phosphorothioate can enhance stability and reduce immunogenicity. Delivery of siRNAs and miRNAs is a major challenge, as they are hydrophilic, negatively charged, and have high molecular weight, making them poorly permeable across biological membranes. Nonviral delivery systems such as cationic polymers, lipids, and nanoparticles are used to facilitate cellular uptake and protect the RNA from degradation. Viral vectors are also used for delivery but pose safety concerns such as immunogenicity and insertional mutagenesis. Both siRNAs and miRNAs have potential as therapeutic agents, but their development faces challenges such as stability, delivery, and off-target effects. Chemical modifications and improved delivery systems are needed to enhance their therapeutic potential. The review highlights the importance of understanding the mechanisms of action, designing effective siRNAs and miRNAs, and developing safe and efficient delivery systems for their clinical application.siRNA and miRNA are non-coding RNAs that regulate gene expression. They have been investigated as potential therapeutic agents for treating diseases such as cancer and infections. While both siRNAs and miRNAs target mRNA for gene silencing, they differ in their mechanisms of action and clinical applications. siRNAs are highly specific and target a single mRNA, whereas miRNAs have multiple targets. Therapeutic approaches for siRNAs involve RNA interference (RNAi) to inhibit mRNA expression, while miRNA-based therapies include miRNA inhibition and replacement. The review discusses the mechanisms, physicochemical properties, delivery, and clinical applications of siRNAs and miRNAs, as well as the challenges in developing them as therapeutics. siRNAs are processed by Dicer into a short dsRNA molecule, which is loaded into the RNA-induced silencing complex (RISC) to cleave target mRNA. miRNAs are processed through a similar pathway but are loaded into the miRISC complex, where they guide the complex to target mRNA for degradation or repression. siRNAs are more specific and can target a single mRNA, while miRNAs regulate multiple mRNAs. Both siRNAs and miRNAs face challenges such as poor stability, delivery issues, and off-target effects. The design of therapeutic siRNAs requires careful consideration of sequence, strand orientation, and G/C content to ensure specificity and efficiency. Off-target effects can occur due to partial complementarity with unintended targets. Strategies to reduce off-target effects include using lower concentrations of siRNAs, pooling multiple siRNAs targeting the same mRNA, and avoiding complementarity with the seed region of mRNA. Chemical modifications such as 2'-O-methyl, 2'-fluoro, and phosphorothioate can enhance stability and reduce immunogenicity. Delivery of siRNAs and miRNAs is a major challenge, as they are hydrophilic, negatively charged, and have high molecular weight, making them poorly permeable across biological membranes. Nonviral delivery systems such as cationic polymers, lipids, and nanoparticles are used to facilitate cellular uptake and protect the RNA from degradation. Viral vectors are also used for delivery but pose safety concerns such as immunogenicity and insertional mutagenesis. Both siRNAs and miRNAs have potential as therapeutic agents, but their development faces challenges such as stability, delivery, and off-target effects. Chemical modifications and improved delivery systems are needed to enhance their therapeutic potential. The review highlights the importance of understanding the mechanisms of action, designing effective siRNAs and miRNAs, and developing safe and efficient delivery systems for their clinical application.