RNA Therapeutics Beyond mRNA- siRNA, Antisense Oligonucleotide and microRNA as next generation pharmaceutical modalities- formulation, delivery and clinical progress
Jul 2026· International Journal of Leading Research Publication· Vol 7· 0 citations· 71 references
TL;DR
RNA therapeutics are a quickly developing discipline with enormous promise to improve precision medicine and offer efficient treatment choices for illnesses that are still challenging to treat with traditional medicines.
Abstract
With highly targeted methods for controlling gene expression and treating a wide range of genetic, metabolic, viral, and cancerous disorders, RNA therapies have become a revolutionary technique in contemporary medicine. The main kinds of RNA (ribonucleic acid) treatments, such as antisense oligonucleotides (ASOs), small interfering RNA (siRNA), and microRNA (miRNA), are thoroughly reviewed in this study along with their methods of action, therapeutic uses, and most recent clinical developments. With a focus on viral and non-viral delivery methods such as lipid nanoparticles, liposomes, polymeric carriers, and viral vectors, this review also covers the formulation and delivery strategies used to enhance the stability, cellular uptake, and target specificity of these compounds. A comprehensive analysis is conducted of current issues, such as nuclease degradation, immune recognition, off-target effects, restricted extrahepatic distribution, and formulation-related hurdles. Furthermore, the expanding clinical value of these technologies is demonstrated by current clinical trials and recent advancements in FDA-approved RNA-based therapies. Promising approaches to circumvent current constraints are also highlighted, such as chemical changes, ligand-targeted delivery systems, formulations based on nanotechnology, and artificial intelligence-assisted therapeutic design. All things considered, RNA therapeutics are a quickly developing discipline with enormous promise to improve precision medicine and offer efficient treatment choices for illnesses that are still challenging to treat with traditional medicines.
A rapidly growing class of medications called RNA therapeutics could transform indi-vidualized treatment and target "undruggable" areas. The different forms of RNA-based treat-ments, such as messenger RNAs (mRNAs), small interfering RNAs (siRNAs), and circular RNAs (circRNAs), are discussed in this paper along with their significance in gene regulation and the treatment of disease. Stability and efficient distribution to target cells are major challeng-es for RNA molecules. Hydrogels, dendrimers, and lipid nanoparticles are being developed to improve RNA therapy pharmacokinetics and cellular absorption. More accurate and efficient therapies are also being made possible by breakthroughs in self-amplifying RNA (saRNA) tech-nology and the application of artificial intelligence in RNA delivery design. The review also dis-cusses RNA modifications and synthetic biology in pharmaceutical design. Although good data from preclinical and clinical trials demonstrate the potential of RNA-based therapeutics, further research is necessary to tackle translational difficulties and improve delivery mechanisms for therapeutic usage. RNA treatments may revolutionize medical research by treating cancer and genetic defects.
Unknown authors· Drug Delivery Letters· 0 citations
INTRODUCTION
Gliomas, particularly Glioblastoma Multiforme (GBM), remain highly lethal despite surgery, radiotherapy, and chemotherapy, largely due to their infiltrative biology, marked molecular heterogeneity, and the restrictive Blood-Brain Barrier. RNA interference (RNAi)-based therapeutics, including Small Interfering RNA (siRNA) and emerging microRNA (miRNA)-modulating strategies, enable targeted silencing of oncogenic drivers. However, their clinical application is constrained by rapid systemic clearance, nuclease-mediated degradation, off-target effects, and inefficient brain delivery.
OBJECTIVE
This review evaluates recent advances in RNA-based precision gene silencing for glioma, with particular focus on siRNA therapeutics, emerging miRNA strategies, nanocarrier-enabled delivery systems, and theranostic integration for imaging-guided therapy.
METHOD
A comprehensive literature search (1998-2026) of PubMed, Scopus, and Google Scholar was performed to identify preclinical and early clinical studies addressing glioma pathobiology, RNA interference mechanisms, siRNA targets, nanocarrier platforms, and imaging-guided theranostic systems, with emphasis on orthotopic models, registered clinical trials, and mechanistically well-characterized datasets.
RESULTS
Non-viral nanocarriers (lipid nanoparticles, bio-reducible polymers, dendrimer-gold, exosomes) enable siRNA protection, BBB penetration, and knockdown of EGFR, STAT3, BCL-2, VEGF, and GLUT-3 in orthotopic glioma models. Emerging miRNA-based strategies, including anti-miR-21 and miR-100 modulation, showed potential for reversing chemoresistance. Combination therapies with temozolomide/doxorubicin produced greater efficacy than single-agent approaches. Theranostic imaging platforms (PET/MRI/SPECT) enabled real-time monitoring of biodistribution and treatment responses.
CONCLUSION
RNA-based theranostic strategies show promising potential for glioma therapy. However, further optimization of delivery systems, improved safety profiles, and successful clinical translation remain necessary.
Small interfering RNAs (siRNAs) are programmable nucleic acids that play key roles in chemical biology and can selectively silence disease-associated genes through RNA interference (RNAi). These programmable nucleic acids have emerged as a powerful class of medicines and chemical biology tools that can rewire tumor-immune signaling, target immunosuppressive genes, stimulate immune responses, and boost the immune system against immune-mediated diseases. Recent success in the rapid synthesis and applications of siRNA highlights the potential of this technology to address previously “undruggable” targets across a range of genetic, metabolic, and oncologic diseases. Despite the potential of these siRNA-based therapies, including those used in cancer immunotherapy, challenges such as off-target effects during delivery, chemical degradation of siRNA in the body, and immunogenicity limit their efficacy. This review provides a comprehensive overview of the chemical biology and chemical modifications inherent to the design of robust siRNA therapies; the nucleic acid structure–function relationships that dictate the cellular mechanisms underlying siRNA-mediated gene silencing and efficacy; and the current clinical landscape and safety of approved siRNA therapeutics for immunotherapy. We examine the growing role of computationally guided design strategies and emerging machine-learning-based methods in optimizing siRNA chemical design, and outline how recent advances in siRNA chemical modification are expected to improve targeted gene modulation in the clinic. Additionally, we examine the role of delivery systems in enhancing siRNA potency, with an emphasis on tumor-targeted and tissue-specific approaches, as well as emerging combination therapies integrating siRNA with chemotherapy, immune checkpoint blockade, siRNA and mRNA co-delivery, and prodrug activation.
Hayden Tobias, Sarah Porter, Isabella M Marcelo et al.· RSC Chemical Biology· 0 citations
Small interfering RNA (siRNA) therapeutics has huge potential for treating many diseases, including those incurable or undruggable by small molecules or antibodies, by harnessing RNA interference (RNAi) to achieve specific silencing of disease-associated genes. To date, all approved siRNA drugs are limited to liver targeting, largely due to delivery challenges. The two siRNA delivery platforms used clinically, namely lipid nanoparticles (LNPs) and N-acetylgalactosamine (GalNAc)-conjugation, are optimized for liver accumulation, restricting broader tissue targeting. Peptides offer a versatile approach to enhance siRNA delivery efficiency by functionalizing nanoparticles as surface ligands to enable specific cell targeting, facilitating cellular uptake and promoting endosomal escape. Alternatively, they can be used as standalone delivery system through complexation or covalent conjugation with siRNA while still fulfilling these roles. Over the years, the development of peptide-based siRNA delivery system has evolved from naturally occurring sequences, rational design, to phage display screening, with emerging machine-learning (ML) approaches expected to accelerate the discovery of novel peptides. This special report highlights the development of peptide-based delivery systems and discusses future directions toward next-generation siRNA delivery platforms to facilitate their successful clinical translation.
Michael Y. T. Chow, J. Lam· Nanomedicine· 0 citations
This review summarizes current and emerging model‐informed drug development applications in oligonucleotide therapeutics, with primary emphasis on siRNAs and complementary insights from ASOs.
Paridhi Gupta, Mindy Magee, Vivaswath S. Ayyar· Journal of clinical pharmaco...· 0 citations
RNA therapeutics have emerged as versatile platforms for gene modulation and protein expression in vaccination, oncology, genetic disorders, and inflammatory diseases. However, their broader clinical application remains limited by inefficient delivery, insufficient tissue specificity, inadequate intracellular bioavailability, and long-term safety concerns. This review examines non-viral and non-lipid RNA nanocarriers from mechanistic and translational perspectives. We outline the cargo-specific delivery requirements of various RNA modalities and analyze polymeric nanoparticles, inorganic nanomaterials, peptide- and protein-based carriers, and virus-like particles as distinct strategies to overcome extracellular, tissue-level, cellular, and intracellular barriers. Cross-platform trade-offs are evaluated based on RNA association and release, cargo compatibility, administration route, biodegradability, immune interactions, and manufacturability. We further discuss how carrier architecture influences biodistribution, intracellular RNA activity, and therapeutic efficacy across major disease areas. Clinically validated lipid nanoparticle (LNP) formulations serve as translational benchmarks, while non-lipid systems are evaluated based on productive delivery, release efficiency, repeat-dose compatibility, long-term material fate, scalability, and regulatory feasibility. By integrating cargo requirements, barrier resolution, intracellular trafficking, and translational benchmarking, this review highlights non-viral and non-lipid nanocarriers as complementary platforms for context-specific RNA therapy.
Mingxia Jiang, Qiannan Cao, Huapan Fang et al.· Journal of Controlled Releas...· 0 citations