With the continuous advancement of precision medicine, small nucleic acid therapeutics are rapidly transitioning from cutting-edge research to clinical reality. 

Unlike traditional small molecules or antibodies that primarily target proteins, these therapies act at the level of gene expression (DNA or mRNA), opening new avenues for previously “undruggable” targets.

As an important participant in the global pharmaceutical supply chain, DengYueMed continues to monitor innovative therapies, including nucleic acid–based drugs, and facilitates their accessibility and distribution in international markets.

This article systematically reviews the core mechanisms and application landscapes of six major classes of small nucleic acid therapeutics.

1. Antisense Oligonucleotides (ASOs): Dual Pathways from Degradation to Modulation

Antisense oligonucleotides (ASOs) are typically single-stranded DNA or RNA analogs of 18–30 nucleotides in length. They regulate gene expression by binding to target RNA via complementary base pairing.

Their mechanisms can be broadly categorized into two main pathways:

1.  RNase H1-dependent degradation: ASOs form DNA–RNA hybrids with target mRNA, recruiting RNase H1 to cleave the RNA strand, leading to rapid mRNA degradation and reduced protein expression.

2.  Steric blocking (non-degradative mechanism): ASOs interfere with RNA function by occupying key regions, including blocking ribosome assembly at the start codon, modulating pre-mRNA splicing, or targeting upstream open reading frames (uORFs).

Clinically, ASOs represent one of the most mature classes of nucleic acid therapeutics, particularly in neurological and rare diseases. Representative drugs include:

● Nusinersen: modulates SMN2 splicing for the treatment of spinal muscular atrophy (SMA)

● Eteplirsen: induces exon skipping for Duchenne muscular dystrophy (DMD)

● Inotersen: degrades TTR mRNA for hereditary transthyretin amyloidosis

Overall, ASOs offer clear mechanisms, flexible design, and broad therapeutic applicability, although delivery—especially to the central nervous system—often requires specialized routes such as intrathecal injection.

2. Aptamers: Structure-Driven High-Specificity Recognition

Aptamers are single-stranded DNA or RNA molecules identified through SELEX technology.

They fold into specific three-dimensional structures that enable high-affinity and high-specificity binding to target molecules, functioning similarly to antibodies.

Their mechanism is fundamentally based on structural recognition rather than sequence complementarity.

Compared to antibodies, aptamers offer several engineering advantages:

● High synthesis efficiency, low cost, and strong batch consistency

● Low immunogenicity and favorable safety profile

● Ease of chemical modification and conjugation, enabling delivery system design

In terms of applications, aptamers can function both as therapeutic agents and as targeting ligands.

For example, Pegaptanib is used for anti-angiogenic therapy. Additionally, aptamers are widely explored as targeting moieties in conjugates with siRNA or chemotherapeutic agents for precision delivery.

3. siRNA: Core Executor of RNA Interference

Small interfering RNA (siRNA) consists of double-stranded RNA molecules approximately 20–25 base pairs in length and serves as a key effector of the RNA interference (RNAi) pathway.

After entering the cell, siRNA is incorporated into the RNA-induced silencing complex (RISC), where Argonaute 2 (AGO2) plays a central role.

The process can be summarized as a precise cleavage system:

● siRNA is loaded into RISC, and the guide strand is retained

● The guide strand pairs perfectly with the target mRNA

● AGO2 cleaves the mRNA at the position corresponding to nucleotides 10–11 of the guide strand

● The cleaved mRNA is degraded, resulting in gene silencing

Representative approved drugs include:

● Patisiran: the first approved siRNA therapy for transthyretin amyloidosis

● Inclisiran: targets PCSK9 for cholesterol reduction in cardiovascular disease

● Givosiran: treats acute hepatic porphyria

The success of siRNA therapeutics is largely driven by GalNAc-mediated delivery, enabling efficient hepatocyte targeting. Applications are now expanding into cardiovascular and metabolic diseases.

4. miRNA: Network-Level Regulators with Broad Impact

MicroRNAs (miRNAs) are endogenous small RNAs generated through multi-step processing involving Drosha and Dicer enzymes.

Mature miRNAs regulate gene expression by partially pairing with the 3′ untranslated region (3′ UTR) of target mRNAs via their seed sequences.

Their defining feature is broad regulatory capacity:

● In most animal cells, miRNAs do not directly cleave mRNA but instead repress translation or promote mRNA decay

● A single miRNA can regulate hundreds of genes

● They form complex gene regulatory networks

Based on these mechanisms, two main therapeutic strategies have emerged:

● miRNA mimics: restore downregulated tumor-suppressive miRNAs

● antagomirs: inhibit overexpressed pathogenic miRNAs

However, their multi-target nature also introduces challenges related to off-target effects and systemic regulation.

5. piRNA: A Genome-Stabilizing Silencing System

PIWI-interacting RNAs (piRNAs) are primarily expressed in germ cells and are typically 26–31 nucleotides long. They function by binding to PIWI proteins and play a critical role in suppressing transposable elements, thereby maintaining genomic stability.

Their regulatory mechanisms operate at two levels:

● In the nucleus, piRNAs induce transcriptional gene silencing (TGS) through chromatin modification

● In the cytoplasm, they mediate post-transcriptional gene silencing (PTGS) via RNA degradation

The unique “ping-pong amplification cycle” further enhances their silencing efficiency.

While piRNAs are mainly associated with the germline, aberrant expression has also been observed in cancers, making them an emerging area of research, though therapeutic development remains in early stages.

6. saRNA: Reversing the Paradigm—From Silencing to Activation

Small activating RNAs (saRNAs) represent a novel class of nucleic acid therapeutics capable of upregulating gene expression, challenging the traditional view that small RNAs only silence genes.

Although structurally similar to siRNA, saRNAs function through a distinct mechanism:

● saRNA associates with AGO2 and translocates into the nucleus

● It targets promoter regions of specific genes

● It recruits transcriptional activation complexes (such as RITA)

● It activates RNA polymerase II, initiating transcription

This mechanism is particularly promising for conditions requiring gene upregulation, such as restoring tumor suppressor gene activity.

Compared to mRNA therapies, saRNAs are smaller, impose a lower delivery burden, and offer more controlled expression profiles.

Conclusion: From Mechanistic Innovation to Global Accessibility

Together, these six classes of nucleic acid therapeutics form a comprehensive framework spanning gene silencing, expression modulation, and transcriptional activation, fundamentally reshaping the paradigm of drug development.

From a current landscape perspective:

● ASOs and siRNAs have entered mature commercialization stages

● Aptamers are evolving into delivery platforms

● miRNAs, piRNAs, and saRNAs remain in exploratory and early development phases

With continued advancements in delivery technologies and industrial infrastructure, nucleic acid therapeutics are poised to become a major therapeutic modality alongside antibodies.

In this evolving landscape, DengYueMed, as a global pharmaceutical distribution and supply chain platform, continues to facilitate the cross-border flow and commercialization of innovative therapies, helping cutting-edge treatments reach patients worldwide more efficiently.