Polynucleotide (PN)

Definition

Polynucleotides (PN) are biopolymers composed of long chains of nucleotide monomers linked by phosphodiester bonds. In the context of regenerative and aesthetic medicine, the term "polynucleotide" refers specifically to high-molecular-weight DNA fragments — typically exceeding 1500 kilodaltons (kDa) — extracted from the reproductive cells of various aquatic species . While PN and PDRN (polydeoxyribonucleotide) share a common biochemical origin, they are distinguished by molecular weight range, extraction source, purification process, and receptor specificity .

Chemical Structure and Molecular Weight

Like PDRN, polynucleotides are composed of deoxyribonucleotide units, each consisting of a deoxyribose sugar, a phosphate group, and one of four nitrogenous bases (adenine, thymine, guanine, or cytosine). These units are connected via 3'-5' phosphodiester bonds to form the sugar-phosphate backbone characteristic of DNA .

The defining structural difference between PN and PDRN lies in chain length and, consequently, molecular weight. PDRN fragments range from 50 to 1500 kDa, while PN preparations typically contain fragments greater than 1500 kDa, sometimes exceeding 3500 kDa . This larger molecular weight gives PN distinct biophysical properties: greater viscoelasticity, longer tissue residence time, and stronger hydrating capacity when injected into the dermis .

Both PN and PDRN retain the double-helix conformation of B-form DNA, but PN fragments are long enough to exhibit more pronounced gel-like behavior in solution, which is clinically relevant for volumizing and hydrating effects .

Sources and Extraction

Polynucleotides are derived from the DNA of aquatic organisms. The most common sources include:

• Salmon (Oncorhynchus keta): The primary source for PDRN-based products such as Rejuran. Salmon DNA is extracted from sperm cells and purified through a standardized pharmaceutical process .
• Trout (Oncorhynchus mykiss): Used for many PN-based injectable products in European markets. Trout-derived PN preparations tend to have higher average molecular weights compared to salmon-derived PDRN .
• Plant sources: Some newer formulations use plant-derived polynucleotides, though these are less studied and primarily appear in cosmetic (topical) products rather than medical injectables.

The extraction process involves cell lysis, protein removal via enzymatic digestion and purification, lipid elimination, and final filtration. For PDRN, an additional fragmentation step produces the smaller molecular weight range. PN products skip or minimize this fragmentation, preserving longer DNA chains .

PN vs PDRN: Key Differences

Although PN and PDRN are both DNA-derived biopolymers used in skin rejuvenation, they differ in several important respects :

| Property | PDRN | PN |

|---|---|---|

| Molecular weight | 50–1500 kDa | >1500 kDa (up to 3500+ kDa) |

| Primary source | Salmon (O. keta) | Trout (O. mykiss), salmon |

| A2A receptor binding | Strong, well-documented | Weaker or indirect |

| Primary mechanism | A2A receptor activation + salvage pathway | Biostimulation + hydration + scaffold effect |

| Viscosity | Lower | Higher (gel-like) |

| Tissue residence | Shorter | Longer |

| Regulatory class | Pharmaceutical (in many markets) | Medical device or cosmetic (varies) |

The most clinically significant distinction is receptor specificity. PDRN's smaller fragments have been extensively demonstrated to activate the adenosine A2A receptor, triggering downstream anti-inflammatory and pro-regenerative signaling cascades . PN, due to its larger molecular size, has reduced direct A2A receptor binding affinity. Instead, PN exerts its effects primarily through biostimulation — acting as a structural scaffold that attracts fibroblasts and promotes extracellular matrix remodeling — and through sustained hydration of dermal tissue .

Mechanism of Action in Skin

Polynucleotides act on the skin through several interconnected pathways :

1. Biostimulation and scaffold effect: When injected into the dermis, the long PN chains create a three-dimensional matrix that serves as a biological scaffold. Fibroblasts migrate toward and adhere to this scaffold, increasing local cell density and collagen production .
2. Hydration: PN chains are highly hydrophilic. Their large molecular weight allows them to bind and retain significant amounts of water within the dermal tissue, improving skin turgor, elasticity, and radiance .
3. Nucleotide salvage pathway: As endogenous nucleases gradually degrade PN fragments, the released nucleotides and nucleosides enter the salvage pathway, providing building blocks for DNA and RNA synthesis in metabolically active or stressed cells .
4. Indirect anti-inflammatory effects: While PN does not bind A2A receptors as effectively as PDRN, the nucleosides released during degradation (particularly adenosine) can still engage A2A signaling, producing mild anti-inflammatory effects over a sustained period .

Clinical Applications

Injectable treatments

PN-based injectables are widely used in aesthetic medicine for skin rejuvenation. Products such as Plinest (trout-derived PN) are administered via micro-injections into the superficial dermis of the face, neck, decolletage, and hands . Clinical studies report improvements in skin hydration, elasticity, fine lines, and overall skin quality following a course of 3–4 sessions spaced 2–4 weeks apart .

Salmon-derived PDRN injectables, such as Rejuran Healer, occupy a related but distinct niche. Rejuran leverages the smaller PDRN fragments for their A2A receptor activity and is particularly popular in South Korea and across Asia .

Topical products

Both PN and PDRN are incorporated into serums, ampoules, and creams marketed for skin repair and anti-aging. In topical formulations, the large molecular weight of PN limits dermal penetration, so these products primarily act on the skin surface and upper epidermis. PDRN, with its smaller fragments, may achieve slightly better penetration, though topical delivery of either molecule is inherently limited compared to injection .

Safety Profile

Both PN and PDRN have established favorable safety profiles. Because they are derived from highly purified DNA with proteins and lipids removed, the risk of immunogenic reaction is very low . DNA sequences from salmon and trout species show minimal cross-reactivity with human immune receptors.

Common side effects of injectable PN are limited to transient, injection-site reactions: mild erythema, swelling, and bruising that typically resolve within 24–72 hours . Serious adverse events are rare. Patients with known fish allergies should inform their clinician prior to treatment, although the high degree of purification generally eliminates allergenic proteins .

Key Takeaway

Polynucleotides (PN) and polydeoxyribonucleotides (PDRN) are both DNA-derived biopolymers used for skin rejuvenation, but they are not interchangeable. PDRN (50–1500 kDa) acts primarily through adenosine A2A receptor activation and the nucleotide salvage pathway, while PN (>1500 kDa) functions mainly as a biostimulatory scaffold and deep hydrator. Both are clinically effective, well-tolerated, and supported by a growing body of evidence — but choosing between them depends on the specific clinical goal, the target tissue, and the desired mechanism of action .