Aptamers are short RNAs that fold
into 3D shapes to bind proteins with
high specificity, enabling blockage
of disease pathways. Approved
intravitreal therapies pegaptanib and
avacincaptad pegol treat forms of
macular degeneration, while trials are
expanding to other retinal diseases,
cancers, and long COVID (1).
Antisense oligonucleotides (ASOs) are short single-stranded RNAs
that bind target mRNAs to block translation, induce degradation, or alter
splicing (2). Approved ASOs like nusinersen and eteplirsen treat rare neuromuscular disorders, with research expanding applications to more tissues
and other rare monogenic disorders (3,4).
MicroRNAs (miRNAs) are small non-coding RNAs that guide RISC to silence mRNAs,
with therapeutics using miRNA mimics to inhibit protein synthesis or miRNA inhibitors
to restore it (6). Clinical trials are exploring them to treat cancer, cardiac dysfunctions,
viral infections, and genetic disorders (7).
In the CRISPR-Cas9 system, single guide RNAs (sgRNAs) direct Cas nucleases
to precise DNA sites for targeted gene editing. Casgevy, the first FDA-approved
CRISPR therapy, edits patients’ blood stem cells for sickle cell disease. Trials continue for cystic fibrosis, viral infections, immune, and cardiovascular disorders (9).
Messenger RNAs (mRNAs) are
transient carriers of genetic information that, due to their modifiability,
function as therapeutics in replacement therapy, cell therapy — for
modifying patients’ cells ex vivo
— and vaccination, most notably
the COVID-19 vaccine (2). Trials are
underway for cancers, cystic fibrosis,
and cardiovascular diseases (3).
Circular RNAs (circRNAs) are
more stable and often less immunogenic than linear mRNAs, making
them promising for next-generation
therapeutics. Scientists are exploring
their use in vaccines, gene therapy,
CAR T cell therapy, and as improved
alternatives to linear forms in other
RNA therapeutics (8).
Self-amplifying RNAs (saRNAs) replicate within cells, boosting
protein expression, reducing required doses, and prolonging immune
or therapeutic responses. These features make them promising for
vaccines, gene therapy, and cancer treatment (10). Zapomeran is the first
saRNA COVID-19 vaccine approved in the European Union and Japan (11).
Replicase
SUPPORTED BY
Gene of
interest
Aptamers can also serve as
delivery vehicles for other therapeutic molecules.
Polymer nanomaterials enable
tunable RNA release and provide stable encapsulation (3).
Carbon and gold nanomaterials
protect RNA from degradation
and enable targeted delivery (3).
RNA conjugates with targeting
molecules like GalNAc boost
specificity, stability,
and delivery (12).
Viral vectors deliver RNA
efficiently but trigger strong
immune responses (9).
Lipid-based nanoparticles
encapsulate RNA, with PEGylation and biomimetic tweaks
improving stability, circulation,
and targeting (3).
Silica nanoparticles offer tunable pores, high RNA loading,
and targeted delivery (3).
miRNA
Target mRNA
Ribosome
RISC
miRNA inhibitor
Degradation
Ribosome
ASO
Target mRNA
Translation arrest Splicing modulation
Small interfering RNAs (siRNAs)
are short double-stranded RNAs
that recruit RNA-induced silencing
complex (RISC) to silence mRNA.
Approved siRNAs such as patisiran
and givosiran treat rare hepatic and
neurological diseases, while trials are
exploring this class to treat various
types of cancers in combination with
other cancer drugs (3,5).
RISC
Target mRNA
siRNA OH
HO
BY ALEJANDRA MANJARREZ, PHD | ILLUSTRATED BY KRISTYN REID
From silencing harmful genes to boosting protein production, RNA therapies are opening new frontiers in medicine, with delivery systems guiding their journey.
EXPLORING THE RNA THERAPEUTICS UNIVERSE
REFERENCES
1. Cesarini, V., Appleton, S.L., De Franciscis, V. & Catalucci, D. The recent blooming of therapeutic aptamers. Mol Aspects Med 102, 101350 (2025).
2. Paunovska, K., Loughrey, D. & Dahlman, J.E. Drug delivery systems for RNA therapeutics. Nat Rev
Genet 23, 265–280 (2022).
3. Damase, T.R. et al. The Limitless Future of RNA Therapeutics. Front Bioeng Biotechnol 9, 628137 (2021).
4. Lauffer, M.C., Van Roon-Mom, W., Aartsma-Rus, A., & N=1 Collaborative. Possibilities and limitations
of antisense oligonucleotide therapies for the treatment of monogenic disorders. Commun Med 4, 6 (2024).
5. Sousa, C. & Videira, M. Dual Approaches in Oncology: The Promise of siRNA and Chemotherapy Combinations in Cancer Therapies. Onco 5, 2 (2025).
6. Zogg, H., Singh, R. & Ro, S. Current Advances in RNA Therapeutics for Human Diseases. IJMS 23,
2736 (2022).
7. Brillante, S., Volpe, M. & Indrieri, A. Advances in MicroRNA Therapeutics: From Preclinical to Clinical
Studies. Hum Gene Ther 35, 628–648 (2024).
8. O’Leary, E., Jiang, Y., Kristensen, L.S., Hansen, T.B. & Kjems, J. The therapeutic potential of circular
RNAs. Nat Rev Genet 26, 230–244 (2025).
9. Mollica, L., Cupaioli, F.A., Rossetti, G. & Chiappori, F. An overview of structural approaches to study
therapeutic RNAs. Front Mol Biosci 9, 1044126 (2022).
10. Parvin, N., Mandal, T.K. & Joo, S.-W. The Impact of COVID-19 on RNA Therapeutics: A Surge in Lipid
Nanoparticles and Alternative Delivery Systems. Pharmaceutics 16, 1366 (2024).
11. Casmil, I.C. et al. The advent of clinical self-amplifying RNA vaccines. Mol Ther 33, 2565–2582
(2025).
12. Chatterjee, S., Bhattacharya, M., Lee, S.-S. & Chakraborty, C. An insight of different classes of RNAbased therapeutic, nanodelivery and clinical status: Current landscape. Curr Res Biotechnol 6, 100150
(2023).
Target DNA
sgRNA
Cas9
Protein
RNaseH1
CLASSES OF RNA-BASED THERAPEUTICS VEHICLES FOR RNA DELIVERY
Targeted RNA delivery faces hurdles from
instability, immune activation, size, charge, and
RNase degradation. Researchers are developing
various delivery platforms to address these
challenges (2,3,10).
Delivery of RNAbased therapeutics
