Aug 2026· Biotechnology and Bioengineering· 0 citations· 93 references
Medicine
TL;DR
This review argues that circular topology should be viewed as an active pharmacologic variable, not merely a stability enhancement, and dissect recent advances in cap-independent translation initiation, including IRES elements and m6A-driven mechanisms, rolling-circle translation for multi-epitope vaccine design, and programmable stability circuits that integrate tumor-microenvironment cues such as miRNA signatures.
Abstract
The topology of RNA therapeutics is emerging as a critical design dimension in precision oncology. Unlike linear mRNA, circular RNA (circRNA) lacks free ends, conferring exceptional resistance to exonuclease degradation and enabling sustained protein expression for days to weeks. Beyond their use as engineered therapeutics, endogenous circRNAs exhibit cancer-associated expression patterns and persistence in biofluids, supporting complementary roles in tumor biology and as candidate biomarkers for diagnosis and longitudinal disease monitoring. This review argues that circular topology should be viewed as an active pharmacologic variable, not merely a stability enhancement. We dissect recent advances in cap-independent translation initiation, including IRES elements and m6A-driven mechanisms, rolling-circle translation for multi-epitope vaccine design, and programmable stability circuits that integrate tumor-microenvironment cues such as miRNA signatures. Delivery innovations are equally transformative: antibody-guided lipid nanoparticles and engineered extracellular vesicles enable increasingly selective RNA delivery, while local depot formulations and organ-selective systemic routes expand therapeutic reach. Safety considerations are re-evaluated as double-edged tools-innate immunogenicity can serve as a self-adjuvant for cancer vaccines, whereas back-splice-junction neoantigens offer both vaccine opportunities and tolerance risks. Recent advances in scarless circularization, topology-sensitive purification, dsRNA depletion, and lyophilized formulations have begun to address key manufacturing bottlenecks, although clinical-scale recovery and process scalability remain insufficiently characterized. Key applications include circRNA cancer vaccines, transient CAR-T/NK cell engineering, tumor-suppressor replacement, and circRNA-encoded bispecific T-cell engagers. The field now requires real-time pharmacokinetic tracking, reproducible and scalable manufacturing, validated liquid-biopsy assays, and indication-specific regulatory pathways to translate circRNA from bench to bedside.
Minimal residual disease (MRD) denotes the persistence of malignant cells below the detection limits of conventional diagnostics and is a principal determinant of relapse and therapeutic failure. Enhancing MRD detection is therefore essential for precision oncology. Tumor‑derived circular RNAs (circRNAs)-covalently closed transcripts defined by back‑splice junctions-have emerged as compelling biomarkers for MRD owing to their exceptional stability, resistance to exonucleases, and enrichment in extracellular vesicles, which together enable reliable detection in biofluids. Beyond these analytical advantages, circRNAs actively participate in tumor biology through miRNA sponging, protein scaffolding, and transcriptional regulation, processes that contribute to epithelial-mesenchymal transition, therapy resistance, and metastatic competence. This review integrates current knowledge of circRNA biogenesis and molecular function, surveys cancer-type-specific circRNA expression signatures, and evaluates evidence for their utility in MRD monitoring across hematologic and solid malignancies. We propose multilayered diagnostic frameworks combining circRNA profiling with circulating tumor DNA (ctDNA), exosomal cargo analysis, and AI‑driven bioinformatics to improve sensitivity, specificity, and longitudinal risk stratification. Finally, we critically examine translational hurdles-preanalytical standardization, assay harmonization, cross‑platform reproducibility, clinical thresholding, and prospective validation-and outline strategic priorities to accelerate clinical implementation of circRNA‑based MRD surveillance for personalized patient management.
T. N. Alramadneh, Hussein salim abed, Sarah Qutayba Badraldin Qutayba Badraldin et al.· Journal of Investigative Med...· 0 citations
This comprehensive review examines the molecular architecture and mechanisms of established platforms in the clinical setting, including mRNA, antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs) and aptamers, alongside next-generation platforms, such as CRISPR-guided systems and circular RNAs (circRNAs).
Konstantina Athanasopoulou, Glykeria N. Daneva, V. Michalopoulou et al.· Current Issues in Molecular...· 0 citations
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.
Avinash Verma, Shaweta Sharma· Drug Delivery Letters· 0 citations
The integration of rational material design, high-throughput screening, artificial intelligence, and interdisciplinary collaboration will be essential to advance next-generation targeted in vivo mRNA cell therapies toward clinical translation.
Danyang Wang, Yumin Li, Jinfeng Deng et al.· Drug Delivery· 0 citations
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
Advances in molecular biology have expanded antimicrobial strategies that traditionally targeted proteins or metabolic pathways to now include RNA, enabling a previously unattainable precision through control of gene expression. The clinical potential of RNA-therapeutics was demonstrated during the COVID-19 pandemic, when mRNA vaccines marked a transformative milestone for RNA-based interventions for viral infections. Increasingly, similar principles are emerging for the treatment of bacterial infections. Antisense oligonucleotides (ASOs) bind complementary mRNA sequences to induce RNase H-mediated degradation or block their translation. Initially developed for genetic and neurodegenerative disorders, ASOs are now emerging as next-generation antibacterials, termed ASOBiotics, designed to silence essential bacterial genes. In this review, we explore the advances of ASO technologies with applications in bacterial pathogens, outlining design considerations while discussing the challenges and opportunities for making precision antibacterial therapeutics.
Jessica B. Kelly, G. Brodie, M. S. Zeden· Current Opinion in Microbiol...· 0 citations
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