1 Chemical Nature and Raw Material Characteristics of PDRN

1.1 PDRN Is a Mixture of DNA Fragments with a Defined Chain-Length Distribution

Polydeoxyribonucleotide (PDRN) is a mixture of DNA fragments composed of deoxyribonucleotides linked through 3′,5′-phosphodiester bonds. PDRN is not a single compound with a fixed molecular weight. Different raw materials may vary considerably in average chain length, molecular weight distribution, single- to double-stranded DNA ratio, purity, and other characteristics.

Conventional pharmaceutical- and research-grade PDRN is generally extracted from the sperm-cell DNA of salmonid fish, such as rainbow trout and chum salmon, and is prepared through tissue separation, DNA purification, controlled fragmentation, and impurity removal. The final raw material contains no intact sperm cells and consists primarily of purified DNA polymer fragments.

The specifications of PDRN used in different studies are not identical. For example, a 2026 topical study used PDRN-850K derived from salmon sperm-cell DNA, with a raw material purity of at least 96%, an average fragment length of approximately 1,200 base pairs, and an average molecular weight not exceeding 850 kDa. These were specific parameters of the raw material used in that study and do not represent a universal standard for all PDRN products.[10]

1.2 Key Parameters Determining the Properties of PDRN Raw Materials

The biological effects of PDRN cannot be assessed solely from designations such as “salmon DNA” or “Sodium DNA.” In skincare products and research formulations, the following parameters directly affect raw material consistency, stability, and bioavailability.

1.3 Basic Metabolic Processes of PDRN in Tissues

After entering a tissue environment containing nucleases, PDRN can be progressively degraded into oligodeoxyribonucleotides, deoxyribonucleotides, deoxyribonucleosides, and nitrogenous bases.

The simplified process can be represented as follows:

PDRN

—endonucleases and exonucleases→ oligodeoxyribonucleotides

—phosphodiesterases→ deoxyribonucleoside monophosphates (dNMPs)

—5′-nucleotidases→ deoxyribonucleosides + inorganic phosphate

Current mechanistic frameworks for PDRN commonly include A2A receptor-related signaling and nucleotide salvage utilization. PDRN degradation products may provide nucleoside or base precursors for salvage pathways. However, direct molecular-binding and metabolic-tracing evidence is still lacking to determine whether its A2A receptor-related effects are mediated by intact PDRN, specific fragments, or other metabolic processes. PDRN also does not function as a carrier of genetic information that introduces new genes into skin cells.

2 Two Major Pathways Through Which PDRN Participates in Skin Repair

Recovery following skin injury involves control of inflammation, cell migration and proliferation, angiogenesis, re-epithelialization, and extracellular matrix remodeling. PDRN mainly participates in these processes through two interrelated pathways:

1. Enhancement of adenosine A2A receptor-related signaling, thereby regulating inflammatory responses, cell survival, and angiogenesis;

2. Following degradation, PDRN may provide salvageable base and deoxyribonucleoside precursors that support maintenance of the nucleotide pool, DNA synthesis, cell proliferation, and damage repair.

These changes further affect keratinocytes, vascular endothelial cells, and fibroblasts, ultimately influencing epidermal integrity and the dermal extracellular matrix.

The principal mechanisms through which PDRN participates in skin repair can be summarized as two interrelated pathways: A2A receptor-related signaling and nucleotide salvage. These pathways further influence inflammatory regulation, angiogenesis, re-epithelialization, and extracellular matrix remodeling, as illustrated below.

PDRN may regulate persistent inflammation and VEGF-related responses through A2A receptor-related signaling. Bioavailable precursors such as deoxyribonucleosides generated by PDRN degradation may replenish the dNTP pool through nucleotide salvage pathways and support DNA synthesis and repair. These effects further influence keratinocytes, fibroblasts, and vascular endothelial cells, promoting epidermal repair and dermal extracellular matrix remodeling. Evidence for the different steps has been derived from cell studies, animal wound models, and studies using specific PDRN preparations.

3 A2A Receptor-Related Signaling: From Inflammation Control to Angiogenesis

3.1 The A2A Receptor and Its Signal Transduction

The adenosine A2A receptor (A2AR) is a G protein-coupled receptor encoded by the ADORA2A gene. Its physiological ligand is adenosine, and the receptor is primarily coupled to the stimulatory G protein Gs.[1]

During tissue hypoxia, mechanical injury, or inflammation, extracellular adenosine triphosphate (ATP) release increases and ATP is progressively converted into adenosine by extracellular nucleotide-metabolizing enzymes:

ATP

—CD39→ ADP

—CD39→ AMP

—CD73→ adenosine

The reactions above describe the conversion of endogenous extracellular ATP into adenosine in injured tissue and do not represent the degradation pathway of PDRN DNA fragments.

After adenosine binds to A2AR, it can activate the Gs protein and adenylyl cyclase:

Adenosine + A2AR → activation of the A2AR–Gs complex → activation of adenylyl cyclase

The principal reaction catalyzed by adenylyl cyclase is:

ATP → 3′,5′-cyclic adenosine monophosphate (cAMP) + pyrophosphate

Cyclic adenosine monophosphate (cAMP) can subsequently regulate protein kinase A (PKA), cAMP response element-binding protein (CREB), and other cell type-dependent signaling pathways.

In immune cells, A2AR signaling generally helps limit persistent pro-inflammatory responses. In endothelial cells and repairing tissues, this signaling can also affect vascular endothelial growth factor (VEGF) and angiogenesis.

3.2 Evidence Linking PDRN to the A2A Receptor

Studies in human skin fibroblasts have shown that both PDRN and adenosine increase cell proliferation. The A2-class receptor antagonist 3,7-dimethyl-1-propargylxanthine (DMPX) markedly attenuated the proliferative effect of PDRN, whereas an A1 receptor antagonist did not produce the same result.[2]

These findings support the involvement of A2-class adenosine receptors in the proliferative effects of PDRN. Together with subsequent studies, the A2A receptor is considered one of the important candidate subtypes. However, this experiment was a receptor-antagonism study rather than a direct binding study between PDRN and A2AR. Direct molecular-binding evidence is still lacking to determine whether intact PDRN binds directly to A2AR and whether intact PDRN, specific fragments, or components arising from other metabolic processes are primarily responsible for the receptor-related effects.

3.3 Regulation of Inflammation and Tissue Protection

Persistent inflammation increases the release of reactive oxygen species, proteolytic enzymes, and pro-inflammatory cytokines, causing continued damage to keratinocytes, fibroblasts, and the extracellular matrix. A2AR-related cAMP signaling can regulate the expression of inflammatory mediators in a cell type-dependent manner, allowing tissue to gradually transition from persistent inflammation toward proliferation and repair.

A 2023 study in human epidermal keratinocytes showed that PDRN reduced the phosphorylation of extracellular signal-regulated kinase (ERK) and downregulated the expression of multiple inflammation-related genes. These results indicate that the effects of PDRN in keratinocytes involve not only proliferation and migration but also regulation of inflammatory signaling.[8]

The anti-inflammatory effect of PDRN does not involve complete suppression of the immune response. Instead, it reduces persistent and damaging inflammatory signals, thereby providing a more stable tissue environment for subsequent cell migration, proliferation, and matrix formation.

3.4 VEGF and Angiogenesis

Tissue repair requires oxygen, glucose, amino acids, and other metabolic substrates. When microcirculation at an injured site is inadequate, fibroblasts and keratinocytes may lack the metabolic conditions required for protein synthesis and cell division, even when they receive proliferative signals.

In a skin-wound model using genetically diabetic mice, PDRN increased VEGF expression, angiogenesis, collagen organization, and wound strength, while promoting wound closure.[4]

In an experimental burn model, PDRN increased microvessel density and platelet endothelial cell adhesion molecule-1 expression, while also promoting re-epithelialization and the deposition of fibronectin and laminin.[5]

These findings indicate that A2AR-related signaling not only affects inflammation but may also improve local angiogenesis through VEGF and endothelial-cell responses, thereby providing repairing cells with a more adequate supply of oxygen and nutrients.

4 Nucleotide Salvage Synthesis: Providing Precursors for Cell Proliferation and DNA Repair

4.1 De Novo Synthesis and Salvage Synthesis

Cells obtain nucleotides through two principal routes:

① De novo synthesis: nucleotides are progressively synthesized from small molecules such as amino acids, ribose-5-phosphate, carbon dioxide, and one-carbon units;

② Salvage synthesis: pre-existing bases and nucleosides are recycled to regenerate nucleotides.

De novo synthesis requires multiple enzymatic reactions and substantial energy expenditure. During hypoxia, nutrient deficiency, or rapid cell proliferation, the recycling of exogenous or endogenous nucleotide degradation products may help maintain the nucleotide supply.

Deoxyribonucleosides generated by PDRN degradation may re-enter the deoxyribonucleotide pool through phosphorylation:

Deoxyribonucleoside + ATP

—corresponding deoxyribonucleoside kinase→ dNMP + ADP

They are subsequently phosphorylated further:

dNMP → dNDP → dNTP

Where:

· dNMP refers to a deoxyribonucleoside monophosphate;

· dNDP refers to a deoxyribonucleoside diphosphate;

· dNTP refers to a deoxyribonucleoside triphosphate.

dNTPs are the direct substrates required by DNA polymerases for DNA replication and repair.

4.2 Significance of Salvage Synthesis for Injured Skin Cells

When fibroblasts and keratinocytes enter the proliferative phase, they need to expand their dNTP pools to replicate the complete genome. Cells damaged by ultraviolet radiation or oxidative stress also require nucleotides for DNA resynthesis after damaged regions have been excised.

An early study in human skin fibroblasts found that both intact PDRN and PDRN digested with deoxyribonuclease promoted cell proliferation and the synthesis of certain secreted proteins. This suggests that shorter nucleotide fragments and their degradation products may retain biological activity and supports the involvement of salvage pathways in cellular responses.[3]

Salvage synthesis does not mean that PDRN fragments are directly incorporated into human chromosomes. PDRN is first degraded, after which cells utilize the resulting bases, deoxyribonucleosides, or deoxyribonucleotides and convert them into dNTPs through their own metabolic enzymes. These dNTPs are ultimately used by the cells’ own DNA replication and repair systems.

4.3 Effects on the Repair of Ultraviolet-Induced DNA Damage

Ultraviolet B (UVB) radiation can induce the formation of cyclobutane pyrimidine dimers (CPDs) in DNA. After the nucleotide excision repair system removes the damaged oligonucleotide fragment containing the CPD, DNA polymerase must use dNTPs to fill the resulting gap, followed by sealing of the strand by DNA ligase.

In human dermal fibroblasts, the addition of PDRN after UVB irradiation accelerated the reduction of CPDs and was accompanied by an enhanced p53 protein response. The researchers proposed that nucleotide precursors supplied by PDRN might support DNA repair synthesis, although p53 and other damage-response mechanisms may also participate in this process.[7]

These findings were obtained from cell-culture experiments and indicate that PDRN may support cellular repair after ultraviolet damage. However, PDRN cannot replace sun protection, nor can these findings be used to infer that topical PDRN can eliminate all ultraviolet-induced damage in human skin.

5 Effects of PDRN on Fibroblasts and the Extracellular Matrix

5.1 Fibroblasts Are the Core Cells Linking the Tissue-Repair and Anti-Aging Effects of PDRN

Fibroblasts are responsible for the synthesis and remodeling of the dermal extracellular matrix (ECM), which primarily includes:

① Type I and type III collagen;

② Elastin and fibrillin;

③ Fibronectin;

④ Glycosaminoglycans;

⑤ Enzymes that regulate matrix degradation and reorganization.

Photoaging and chronic inflammation reduce fibroblast proliferation, migration, and matrix-synthesis capacity, while also disrupting the mechanical support provided to cells by collagen fibers. The effects of PDRN on dermal structure are primarily based on its regulation of fibroblast function.

5.2 ERK Signaling and Collagen Accumulation

A 2023 study showed that PDRN promoted the proliferation and migration of human dermal fibroblasts and increased ERK phosphorylation. An ERK inhibitor attenuated PDRN-induced cell proliferation, migration, and collagen accumulation, indicating that ERK participates in the fibroblast response to PDRN.[8]

In that study, PDRN increased markers associated with type I procollagen and type III collagen and reduced the expression of the matrix metalloproteinases (MMPs) MMP-1, MMP-2, and MMP-3.

It should be noted that regulation of ERK by PDRN differs according to cell type:

① In fibroblasts, PDRN increases ERK phosphorylation, which is associated with proliferation and collagen accumulation;

② In keratinocytes, PDRN decreases ERK phosphorylation and reduces the expression of pro-inflammatory genes.

Therefore, PDRN does not regulate all skin cells in the same direction, but instead affects different repair processes according to cell type.

5.3 PI3K–Akt, TGF-β/Smad, and Intracellular Homeostasis

A 2026 study used a specific PDRN-850K preparation to treat human dermal fibroblasts under basal conditions and observed the following changes:

1. Enhanced phosphoinositide 3-kinase–protein kinase B (PI3K–Akt) signaling;

2. Increased transforming growth factor-β (TGF-β) expression and Smad2/3 phosphorylation;

3. Increased autophagy-related LC3-II and decreased SQSTM1/p62;

4. Increased expression of the COL1A1, COL3A1, and ELN genes.

Inhibition of PI3K, the TGF-β receptor, or the autophagic process each attenuated the PDRN-850K-induced increases in collagen- and elastin-related gene expression.[10]

These signals perform different functions:

① PI3K–Akt: supports cell survival, metabolism, and protein synthesis;

② TGF-β/Smad: regulates collagen transcription and matrix organization;

③ Autophagy-related processes: remove damaged cellular components and maintain protein and organelle homeostasis.

The study used PDRN-850K with defined chain-length and molecular-weight parameters. Its findings cannot be directly extrapolated to Sodium DNA or PDRN raw materials of all sources and specifications.

5.4 Matrix Remodeling Is Not Simply an Increase in Collagen Quantity

Skin repair requires both the synthesis of new matrix and the degradation and rearrangement of old matrix. MMPs participate in the physiological turnover of collagen, elastic fibers, and other matrix proteins. Complete inhibition of MMPs is not consistent with normal tissue remodeling.

In the 2026 PDRN-850K study, COL1A1, COL3A1, and ELN were markedly increased, whereas MMP1 did not decrease significantly. This suggests that the effect of PDRN on the matrix does not necessarily involve the simultaneous reduction of all degradative enzymes. Instead, it may shift the matrix balance toward repair by increasing synthetic capacity.[10]

6 How PDRN Coordinates Different Cell Types in the Skin

The tissue-repair effects of PDRN arise from the coordination of responses among multiple cell types rather than from fibroblasts alone.

7 Anti-Aging and Pigmentation-Regulating Effects of PDRN

7.1 Basis for the Effects of PDRN on Photoaged Skin

Photoaged skin commonly exhibits the following features simultaneously:

① Chronic low-grade inflammation;

② Accumulation of oxidative and DNA damage;

③ Decline in fibroblast function;

④ Reduced collagen synthesis;

⑤ Increased MMP-related matrix degradation;

⑥ Disorganization of elastic-fiber architecture.

PDRN acts through inflammatory regulation, nucleotide salvage, and fibroblast-mediated matrix synthesis. Its anti-aging effects are primarily manifested as support for the repair of damaged tissues.

A 2026 PDRN-850K study showed that an eye cream containing 0.1% PDRN-850K increased viable epidermal thickness in UV-damaged ex vivo human skin and increased the expression of several collagens, elastin, fibrillin-1, and the mechanotransduction-related protein YAP.[10] It should be noted that UV-damaged skin treated only with culture medium was used as the negative control in this ex vivo experiment, and no vehicle-matched eye cream without PDRN was included. Therefore, the contribution of the formulation vehicle to the observed results cannot be completely excluded.

The same study also conducted a 28-day randomized, double-blind, split-face, within-subject controlled trial in 31 women aged 35–55 years, comparing a 0.1% PDRN-850K eye cream with a vehicle-matched 0.1% retinol eye cream. The PDRN group showed greater improvements than the retinol group in certain measures of periorbital wrinkles, dermal thickness, dermal density, skin elasticity, and firmness.[10]

The study duration was short and the sample size was limited. Early changes in skin thickness and wrinkles may also have included hydration and temporary plumping effects. The findings can be regarded as preliminary short-term human evidence for this specific PDRN-850K formulation relative to a vehicle-matched retinol formulation, but they do not indicate that all PDRN skincare products have the same effects.

7.2 Pigmentation Regulation Is an Ancillary Effect

A 2016 cell study showed that PDRN reduced melanin content and tyrosinase activity in murine Mel-Ab melanocytes and downregulated microphthalmia-associated transcription factor (MITF), tyrosinase, and tyrosinase-related protein-1. In a human melanocyte–keratinocyte co-culture system, PDRN reduced melanin content.[9]

The human observation in that study included only six women and used intradermal injections administered once every four weeks for a total of three treatments. Current evidence is insufficient to confirm that conventional topical PDRN has a stable, independent depigmenting effect.

8 The Stratum Corneum Is the Primary Limiting Factor for Topical PDRN

PDRN has a relatively high molecular weight, is hydrophilic, and contains multiple negatively charged phosphate groups. The intact stratum corneum is composed mainly of corneocytes and lipid lamellae and forms a strong barrier against water-soluble nucleic acid macromolecules of this type.

The 2026 PDRN-850K study used reconstructed epidermis, ex vivo porcine skin, and in vivo Raman spectroscopy and observed that PDRN-related signals entered the viable epidermal region over time. Signals in deeper skin layers were also observed in the fluorescently labeled porcine skin experiment.[10] However, the in vivo Raman assessment of the actual 0.1% PDRN-850K eye cream was conducted on the forearm skin of only one participant and therefore represents an exploratory finding.

These findings support the possibility of topical delivery for this specific PDRN-850K preparation, but the following limitations remain:

1. Raman spectroscopy cannot completely exclude signals from endogenous nucleic acids in the skin;

2. Fluorescent labeling may alter the physical properties of PDRN;

3. Detection of a signal in the viable epidermis does not indicate that intact PDRN has entered cells;

4. The reduction in Raman signals caused by cytochalasin D only supports live cell-dependent or endocytosis-sensitive behavior. It does not identify a specific endocytic pathway or explain how PDRN initially crosses the stratum corneum;

5. Delivery outcomes are affected by molecular weight, vehicle, applied dose, and skin condition.

Findings from topical studies cannot be directly inferred from injection or open-wound studies. Intradermal injection bypasses the stratum corneum, whereas conventional skincare products must first address retention on the skin surface and delivery across the stratum corneum.

9 Scope of Applicability of the Evidence for PDRN

A randomized, double-blind, placebo-controlled clinical trial conducted in 2014 included 216 patients with difficult-to-heal diabetic foot ulcers. PDRN was administered through intramuscular and perilesional injections. After eight weeks of treatment, it increased the wound-closure rate, shortened the median healing time, and increased the re-epithelialized area.[6]

These findings demonstrate that a specific pharmaceutical PDRN preparation has reparative effects in a specific type of wound and with a specific route of administration. However, they cannot be used directly to predict the effects of conventional topical serums on intact skin.

10 Classification and Research Applications of Representative Chemicals Related to PDRN Metabolism, A2A Receptor Signaling, and Skin Matrix Remodeling

Table 1. Core PDRN Raw Materials, Source Comparators, and Quantitative Reference Materials

Table 2. Products Related to PDRN Degradation, Base Composition, and Nucleotide Salvage Synthesis

Table 3. Products Related to the Adenosine A2A Receptor, Extracellular Purine Metabolism, and Cyclic Adenosine Monophosphate Signaling

Table 4. Products Related to Fibroblast Signaling, Cellular Uptake, and Extracellular Matrix Remodeling

Note: The products listed above are representative Aladdin products related to scientific research and formulation studies. Additional product specifications, grades, and certificate of analysis information can be retrieved from the Aladdin website using the product name, CAS number, or catalog number.

References

[1] IUPHAR/BPS Guide to PHARMACOLOGY. A2A receptor: ADORA2A.

[2] Thellung S, Florio T, Maragliano A, Cattarini G, Schettini G. Polydeoxyribonucleotides enhance the proliferation of human skin fibroblasts: involvement of A2 purinergic receptor subtypes. Life Sciences. 1999;64(18):1661–1674. doi:10.1016/S0024-3205(99)00104-6.

[3] Sini P, Denti A, Cattarini G, Daglio M, Tira ME, Balduini C. Effect of polydeoxyribonucleotides on human fibroblasts in primary culture. Cell Biochemistry and Function. 1999;17(2):107–114. doi:10.1002/(SICI)1099-0844(199906)17:2<107::AID-CBF815>3.0.CO;2-#.

[4] Galeano M, Bitto A, Altavilla D, et al. Polydeoxyribonucleotide stimulates angiogenesis and wound healing in the genetically diabetic mouse. Wound Repair and Regeneration. 2008;16(2):208–217. doi:10.1111/j.1524-475X.2008.00361.x.

[5] Bitto A, Galeano M, Squadrito F, et al. Polydeoxyribonucleotide improves angiogenesis and wound healing in experimental thermal injury. Critical Care Medicine. 2008;36(5):1594–1602. doi:10.1097/CCM.0b013e318170ab5c.

[6] Squadrito F, Bitto A, Altavilla D, et al. The effect of PDRN, an adenosine receptor A2A agonist, on the healing of chronic diabetic foot ulcers: results of a clinical trial. The Journal of Clinical Endocrinology & Metabolism. 2014;99(5):E746–E753. doi:10.1210/jc.2013-3569.

[7] Belletti S, Uggeri J, Gatti R, Govoni P, Guizzardi S. Polydeoxyribonucleotide promotes cyclobutane pyrimidine dimer repair in UVB-exposed dermal fibroblasts. Photodermatology, Photoimmunology & Photomedicine. 2007;23(6):242–249. doi:10.1111/j.1600-0781.2007.00320.x.

[8] Shin SM, Baek EJ, Kim KH, Kim KJ, Park EJ. Polydeoxyribonucleotide exerts opposing effects on ERK activity in human skin keratinocytes and fibroblasts. Molecular Medicine Reports. 2023;28(2):148. doi:10.3892/mmr.2023.13035.

[9] Noh TK, Chung BY, Kim SY, et al. Novel anti-melanogenesis properties of polydeoxyribonucleotide, a popular wound healing booster. International Journal of Molecular Sciences. 2016;17(9):1448. doi:10.3390/ijms17091448.

[10] Ye R, Wang Q, Du L, Li L, Hu F. Topical medium-length PDRN enhances dermal extracellular matrix repair in photodamaged skin via PI3K–Akt/TGF-β–regulated pathways. PLOS One. 2026;21(7):e0350905. doi:10.1371/journal.pone.0350905.

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