Medicinal plants, as a primary source of natural metabolites with specific pharmacological activities for humans, have long been a research focus^[1]. In ancient civilizations such as China, India, and Egypt, the use of medicinal plants to treat various diseases dates back 5,000 years. Even in the current era of widespread modern pharmaceuticals, they remain widely used^[2], playing an essential role in disease prevention, treatment, and health maintenance. Traditionally, research on the active components of medicinal plants has primarily focused on secondary metabolites, such as alkaloids^[3], flavonoids^[4], quinones^[5], and terpenoids^[6], while nucleic acids have long been regarded solely as genetic material. These nucleic acids (including DNA, mRNA, siRNA, miRNA, and so on) carry plant cells’ genetic information and participate in key physiological processes such as gene expression, protein synthesis, and cell proliferation and differentiation. During processing or digestion, these nucleic acids are degraded into smaller molecules like nucleotides and deoxyribonucleotides, which are then absorbed and utilized by the human body (as shown in Figure 1). However, in recent years, researchers increasingly recognize that nucleic acids in medicinal plants may represent one of the key active components responsible for their pharmacological effects^[7].

Research on medicinal plant-derived nucleic acids as active components has gradually deepened, from basic discovery to functional verification. In 1998, Fire et al. discovered the phenomenon of double-stranded RNA interference. They found that exogenous double-stranded RNA introduced into Caenorhabditis elegans triggers gene silencing by binding to endogenous messenger RNA (mRNA) transcripts, and this inhibitory effect is markedly stronger than that induced by purified single-stranded RNA. This landmark finding revealed that nucleic acids serve not only as genetic carriers but can also participate in regulatory biological processes^[8]. In 2011, Zhang et al. discovered that plant-derived small nucleic acids can enter human blood and tissues through dietary intake. Once internalized, these small nucleic acids influence physiological functions by regulating target gene expression, thereby exerting biological effects and, for the first time, confirming the cross-kingdom regulatory effect of plant-derived small RNAs in mammals^[9]. In 2019, Huang et al. demonstrated that small nucleic acids can be fully extracted from various medicinal plants even after boiling decoction, which provided experimental support for the clinical application of medicinal plant-derived nucleic acids through oral administration^[10]. Extensive research has now confirmed that nucleic acids show significant therapeutic efficacy and pharmaceutical potential in immune modulation^[11], antitumor activity^[12], antiviral effects^[13], and other areas. This review summarizes the types of nucleic acids in medicinal plants, their extraction techniques, pharmacological properties, mechanisms of action, and future research and development prospects, and it is intended to provide a scientific reference for further in-depth investigations in this emerging field.

Medicinal plants contain a rich repertoire of nucleic acids, including both DNA and RNA. As functional molecules with remarkable regulatory potential and pharmaceutical value, RNAs have emerged as the core focus of current research on medicinal plant-derived bioactive nucleic acids. Based on their protein-coding capacity, cellular RNAs can be broadly classified into coding RNAs (mRNA) and non-coding RNAs (ncRNAs)^[14]. NcRNAs refer to RNA molecules that do not encode proteins, and according to their length, they can be divided into small ncRNAs (sncRNAs, < 200 nt) and long ncRNAs (lncRNAs, > 200 nt). Among these, small regulatory RNAs, typically composed of 20-40 nucleotides, have attracted extensive attention and become key targets for identifying novel active components from medicinal plants^[15].

Current research primarily focuses on two major sRNAs: small interfering RNA (siRNA) and microRNA (miRNA)^[16]. RNA interference (RNAi) represents an evolutionarily conserved post-transcriptional gene regulatory mechanism. Since its discovery in Caenorhabditis elegans in 1998, it has reshaped the landscape of drug development^[8,17]. siRNAs selectively degrade targeted mRNAs before translation, preventing their translation into amino acids and subsequent protein synthesis. By silencing the gene encoding these mRNAs, it blocks the production of abnormal or harmful proteins^[18]. In contrast, miRNAs modulate gene expression by base-pairing with target mRNAs, leading to suppressed translation or accelerated degradation of target transcripts at the post-transcriptional level. This regulatory mode ultimately shapes various physiological processes in organisms^[14].

However, it is noteworthy that in contrast to the extensive mismatches observed for most animal miRNA binding sites, many plant miRNAs bind their targets with perfect or near-perfect complementarity^[19]. Accumulating evidence suggests that plant-derived miRNAs from medicinal plants can survive in the human body and exert pharmacological effects via cross-kingdom regulation of human gene expression^[20]. Furthermore, combined comparative genomic analysis revealed that more than 60% of human protein-coding genes harbor miRNA binding sites maintained by evolutionary purifying selection^[21], providing a theoretical basis for multi-target regulation by exogenous plant-derived miRNAs. Accordingly, plant-derived miRNAs may participate in diverse human physiological and pathological processes and represent promising novel active constituents from medicinal plants^[22,23]. These discoveries have sparked widespread research interest in medicinal plant-derived miRNAs. Meanwhile, imbalances in endogenous miRNA expression are a key factor in the onset and development of numerous diseases, including malignant tumors. Exogenous miRNA supplementation to restore regulatory effects offers novel therapeutic strategies for disease treatment. Furthermore, based on the property that a single miRNA can bind multiple target sequences, a single miRNA can simultaneously act on multiple critical nodes in disease pathways. This feature suggests the therapeutic potential of miRNA therapy against various diseases^[14]. Accordingly, this review focuses on recent research progress on miRNAs derived from medicinal plants, and also supplements the research status of other ncRNAs and functional DNA fragments in medicinal plants.

miRNAs are critical regulatory nucleic acids controlling extensive gene expression networks in organisms. Combined comparative genomic analysis revealed that more than 60% of human protein-coding genes harbor miRNA binding sites maintained by purifying selection^[21], making miRNA-based therapeutics an attractive research hotspot. To date, multiple types of approved synthetic nucleic acid therapeutics, such as antisense oligonucleotides (ASOs), siRNAs, and mRNA vaccines, have validated the druggability of nucleic acid molecules [Supplementary Table 1]^[84]. Meanwhile, a series of synthetic miRNA-targeted oligonucleotides have advanced into clinical trials, including miRNA mimics and anti-miR inhibitors [Table 5].

Two mainstream design strategies are adopted for synthetic miRNA therapeutics: supplementation of miRNAs with active functions via miRNA mimics, and silencing pathogenic miRNAs using synthetic antisense inhibitors^[94]. Nevertheless, although these candidates exhibit promising effects in preclinical experiments, their clinical translation is hampered by multiple in vivo obstacles. Naked synthetic miRNAs are rapidly degraded by nucleases and undergo fast renal clearance, leading to low bioavailability and suboptimal pharmacokinetic profiles^[95-98]. Widely explored delivery carriers, including lipid nanoparticles, conventional liposomes, and extracellular vesicles, still have inherent limitations such as restricted tissue targeting, circulation instability, and barriers to standardized large-scale manufacture^[99-101]. Furthermore, off-target effects, potential immunogenicity, and imperfect industrial and clinical evaluation frameworks further restrict their broad clinical application^[102-107].

Against this background, naturally occurring nucleic acids derived from medicinal plants represent a promising alternative resource. Growing evidence confirms that plant endogenous miRNAs can achieve cross-kingdom regulation and modulate gene expression within mammalian cells. Distinct from chemically synthesized miRNA oligonucleotides, plant-derived nucleic acids exist within complex herbal matrices. Coexisting phytochemical constituents in medicinal plant extracts may naturally improve nucleic acid stability and facilitate in vivo delivery. In addition, plant-originated miRNAs generally possess relatively low immunogenicity and multi-target regulatory characteristics, matching the holistic pharmacological features of herbal medicines.

Even so, the exploitation of nucleic acids from medicinal plants remains in the preliminary stage. Systematic in vivo studies are still required to characterize the absorption, distribution and functional persistence of plant miRNAs after administration, verify cross-kingdom bioactivity, and develop suitable preparation strategies. Breaking through these limitations will help unlock the pharmaceutical potential of native nucleic acids in medicinal plants and provide new candidates to complement synthetic miRNA therapeutics.

This review systematically sorts out the classification, tissue distribution, optimized extraction strategies, multi-layered in vivo stabilization mechanisms, and cross-kingdom pharmacological regulatory activities of nucleic acids represented by miRNAs derived from medicinal plants. Whereas long-standing research has focused on herbal secondary metabolites such as flavonoids and terpenoids, plant-endogenous miRNAs have emerged as a novel class of orally bioactive natural components that may mediate interspecies gene regulation in mammals. Multiple intrinsic structural features and extrinsic transport pathways jointly maintain their biological activity amid harsh gastrointestinal and circulatory environments, including terminal 2’-O-methylation, high CG base composition, stable hairpin secondary conformations, low-pH-dependent SIDT1-mediated gastric epithelial absorption, and lipid encapsulation within plant exosome-like nanovesicles.

Cumulative experiments have validated the broad-spectrum therapeutic potential of medicinal plant miRNAs covering antitumor, lipid metabolism regulation, antiviral, anti-inflammatory, and cardiovascular protective effects. Currently, two core development frameworks dominate synthetic miRNA therapeutics: supplementing tumor-suppressive signals via chemically modified miRNA mimics, and silencing oncogenic transcripts through synthetic complementary miRNA inhibitors. Despite their preclinical efficacy, synthetic nucleic acid drugs face prominent translational obstacles, including rapid nuclease degradation, low oral bioavailability, off-target interference, and immunogenic risks. In contrast, medicinal plant miRNAs possess unique translational advantages after thousands of years of oral screening in traditional Asian herbal therapy, featuring superior biocompatibility, low adverse reaction rates, and minimal immunogenicity relative to artificially synthesized RNA agents. Nevertheless, prominent research bottlenecks still restrict their clinical translation: synergistic regulatory networks between plant miRNAs and coexisting herbal secondary metabolites remain insufficiently clarified, and standardized oral delivery carriers that sustain miRNA stability during in vivo circulation have not been fully established.

Building on the current research gaps summarized above, future work should prioritize several interconnected research orientations to advance the translational development of medicinal plant-derived miRNA therapeutics. First, multi-omics analytical systems combining transcriptomics, proteomics, and metabolomics should be deployed to systematically decode the synergistic cross-regulatory relationships between plant miRNAs and herbal phytochemicals, while rigorous in vivo trials are required to resolve ongoing academic disputes regarding the oral bioavailability, intestinal absorption efficiency, and tissue distribution characteristics of dietary plant miRNAs. Second, species-specific extraction workflows tailored to diverse medicinal herbs and traditional decoction processing modes need to be standardized to eliminate interference from polyphenols and polysaccharides and improve the yield and integrity of recovered miRNAs; drawing on the outstanding protective performance of natural nanovesicles, low-cost natural vesicle delivery platforms should be developed to strengthen miRNA tolerance to digestive stress. Third, scalable isolation, surface modification, and tissue-targeted transformation technologies for plant-derived exosome-like nanovesicles should be explored, and quantitative pharmacokinetic assessments of encapsulated plant miRNAs need to be performed in mammalian models to characterize their intestinal uptake and systemic metabolic profiles. Fourth, a complete preclinical safety evaluation system dedicated to oral plant miRNA preparations must be constructed to systematically assess acute and chronic toxicity, immunogenicity, and long-term off-target gene interference; unified quality control indicators, mass production specifications, and clinical trial evaluation criteria also need to be formulated to support the industrialization of natural plant nucleic acid drugs as complementary alternatives to synthetic RNA therapeutics. Additionally, high-throughput small RNA sequencing and degradome analysis should be applied to excavate novel functional miRNAs from underexplored medicinal plant varieties, enriching the resource library of natural regulatory nucleic acids for new drug screening and development.