The Promise of Polynucleotides in Targeted DNA Repair for Aesthetic Regeneration

We live in a world where our skin is constantly under siege from UV radiation, environmental toxins, pollutants, and oxidative stress. Aging, as elegantly stated by Dr. David Sinclair, is largely the accumulation of DNA damage over time, compounded by the decline in cellular repair mechanisms.

In aesthetic medicine, we are not simply battling wrinkles; we are working to restore biologic integrity at the cellular level. Polynucleotides offer a scientifically supported, multi-targeted strategy to combat aging by aiding in DNA repair, improving mitochondrial function, and restoring homeostasis in dermal fibroblasts. Their unique mechanism of action and measurable clinical results position polynucleotides as a next-generation modality in regenerative aesthetic practice.

HOW POLYNUCLEOTIDES WORK

Polynucleotides are highly purified fragments of DNA chains, typically sourced from salmon or rainbow trout sperm, due to the high concentration of nuclear material and minimal organelle content. Despite the animal origin, multiple randomized controlled trials have confirmed that these substances are non-antigenic in most individuals. That said, patients with known fish or salmon allergies should be screened prior to treatment.

In the body, polynucleotides are rapidly broken down into nucleotides—adenine, cytosine, guanine, and thymine—that are the foundational units of DNA. They act through two key mechanisms:

Salvage Pathway

Once introduced into the skin via microneedling or laser-assisted channels, these DNA fragments are cleaved by nucleases in the extracellular space. The resulting nucleotides are then recycled by fibroblasts for use in DNA replication and repair, which is especially useful in cells exposed to UV radiation or oxidative stress. This process leads to accelerated skin regeneration at sites of damage.

A2A Receptor-Mediated Pathway

A portion of these polynucleotide fragments, particularly adenosine, binds to the A2A receptors on dermal fibroblasts. This triggers a cascade of regenerative and anti-inflammatory effects, including:

• Increased vascular endothelial growth factor (VEGF) for improved angiogenesis and perfusion
• Collagen production for fibroblast activation and dermal remodeling
• Reduced IL-6 for suppression of chronic low-grade inflammation
• Improved cyclic AMP signaling for activation of transcription factors that promote cell survival and repair

Together, these pathways not only enhance the repair of damaged cells but also modulate the inflammatory environment, a phenomenon now understood as inflammaging—chronic inflammation that accelerates skin aging.

POLYNUCLEOTIDE NOMENCLATURE

Anyone who has been confused by the acronyms—PN, PDRN, PDN, or DNA fragments—is not alone. Initially, these products were labeled using their molecular descriptors (eg, polydeoxyribonucleotides). However, amid public concern around RNA-based vaccines and genetic terminology, manufacturers simplified the names to make them more accessible and consumer-friendly.

Despite the branding, most of these agents operate through similar mechanisms: providing DNA repair substrates and receptor-level signaling to improve skin quality, elasticity, pigmentation, and hydration.

DELIVERY METHODS

Polynucleotides degrade within 2 to 3 hours in vivo, making delivery strategy critical. Common techniques include microneedling (depth varies depending on treatment goals), laser-assisted drug delivery, and jet injectors/electroporation devices.

Microneedling depth is typically targeted to the papillary or reticular dermis, depending on which fibroblast population is the intended target. In clinical practice, I often make additional passes over areas of pigmentation or photodamage, enhancing delivery to the most compromised zones.

Multiple sessions are required—typically 3 to 4 spaced at 2- to 4-week intervals—to overcome rapid enzymatic breakdown and support sustained remodeling.

SCIENTIFIC EVIDENCE AND MECHANISTIC VALIDATION

Skeptics often ask whether it is the microneedling that is working or the polynucleotides. Controlled studies offer clarity.

One key study showed a dose-dependent increase in collagen synthesis when polynucleotides were used, either alone or in combination with hyaluronic acid (HA). Compared across 3 concentrations (0.1%, 0.5%, 1.0%), collagen production increased with polynucleotides alone, and even more so when combined with HA.

Additionally, polynucleotides increase P53 protein expression, a critical marker of DNA damage response; improve mitochondrial density and mitochondrial DNA replication, enhancing cellular energy; and suppress matrix metalloproteinases (MMPs) and elastase, thereby slowing collagen breakdown.

Taken together, these findings support the notion that polynucleotides go beyond simple moisturization or trauma-induced healing. They are biologically active agents that improve both structural and functional aspects of dermal health.

Still, while the early evidence is promising, more rigorous data are needed:

• Larger non-industry–sponsored randomized controlled trials
• Standardized treatment protocols
• Longitudinal studies to assess durability of results
• Comparative trials vs PRP, HA, and other biologics

These will help move polynucleotides from the realm of anecdotal enthusiasm into evidence-based best practice.

INTERRUPTING AGING

Aging is not just a surface phenomenon; it is the visible manifestation of cumulative molecular damage. Polynucleotides offer us a compelling tool to interrupt that process at its source.

Through both salvage-based DNA repair and receptor-mediated collagen and angiogenesis pathways, polynucleotides are proving to be an indispensable ally in regenerative aesthetics. As our understanding of their mechanisms deepens and clinical evidence accumulates, I believe they will become a cornerstone in skin rejuvenation protocols.

The future of aesthetics is not just about lifting or filling; it is about restoring and rebuilding from within. 

Editor’s note: This article is based on a presentation delivered at the 2025 Genesis: Innovations in Aesthetic Regenerative Medicine Meeting.