Polynucleotides: The Science Behind the Skin Trend

Polynucleotides: The Science Behind the Skin Trend

Polynucleotides (PNs) are emerging as important regenerative injectables in aesthetics, but most of what we know about them comes from broader wound-healing and regenerative medicine research rather than cosmetic trials.

What Polynucleotides Are and How They Were Discovered

Polynucleotides are chains of nucleotides, the basic building blocks of DNA and RNA, first characterised in the late 19th and early 20th centuries as scientists unravelled the chemical nature of nucleic acids and genetic material. A specific class used clinically in regeneration is polydeoxyribonucleotide (PDRN), a purified DNA fragment mixture (typically 50-1500 kDa) originally derived from salmon trout or sturgeon sperm, which was later developed into a registered drug for tissue repair and ischaemic conditions. Preclinical work showed that these DNA fragments had pro-healing and anti-inflammatory effects, prompting development programmes in wound care, diabetic ulcers and other chronic injury states before they were repositioned into aesthetic medicine.

Cellular Mechanisms: How Polynucleotides Work

Most of the mechanistic evidence comes from in vitro and animal studies on PDRN/PN rather than branded skin boosters.

Adenosine A2A Receptor Activation and Angiogenesis

Multiple studies demonstrate that PDRN acts as an agonist at the adenosine A2A receptor, triggering downstream pathways that promote angiogenesis and tissue repair. In diabetic wound models, these effects are blocked by A2A antagonists such as DMPX, confirming that the receptor is central to the mechanism. Activation of A2A signalling increases expression of pro-angiogenic factors like VEGF, CD31, transglutaminase-II and angiopoietins, leading to increased microvascular density in healing tissue.

Fibroblast Proliferation and Extracellular Matrix Synthesis

In vitro, PDRN and related PN preparations stimulate proliferation and migration of human dermal fibroblasts and keratinocytes, with associated upregulation of collagen synthesis. Systematic reviews of PDRN in wound healing report enhanced granulation tissue formation, increased collagen deposition and faster re-epithelialisation across different models, suggesting that PNs help restore extracellular matrix architecture rather than simply filling space.

Modulation of Inflammation and Cell-Cycle Regulation

PDRN reduces pro-inflammatory cytokines such as TNF-alpha and can modulate nitric oxide production, shifting the wound microenvironment towards resolution rather than chronic inflammation. In diabetic models, PDRN has been shown to stimulate cell-cycle progression in granulation tissue by activating cyclins and down-regulating inhibitors such as p15 and p27, thereby rescuing impaired cell proliferation in metabolically compromised conditions. This combination of pro-angiogenic, pro-proliferative and anti-inflammatory actions underpins their classification as regenerative rather than purely biostimulatory agents.

Antioxidant and DNA Salvage Effects

DNA fragments can act as free-radical scavengers and contribute nucleosides to cellular salvage pathways, theoretically supporting ATP generation and DNA repair in stressed cells, although this area is less well-defined. Overall, the mechanistic picture is of a multi-target agent that nudges damaged or senescent tissue back towards a more youthful, better-vascularised and less inflamed state.

Evidence for Aesthetic Use

High-purity PN injectables have only recently been evaluated specifically for aesthetic indications.

A 2024 narrative systematic review of polynucleotides in aesthetic medicine concluded that PNs show promising potential for biorevitalisation and skin quality improvement, but emphasised the lack of standardised protocols and the need for rigorous, high-quality trials. Reported aesthetic outcomes across small studies and case series include improvements in fine lines, elasticity, texture and skin hydration, particularly in the periorbital region and photo-damaged skin, with generally favourable safety profiles.

A prospective study using a PN high-purification technology device in Asian skin involved three intradermal treatment sessions at 0, 4 and 8 weeks, with follow-up to 6 months. Objective 3D imaging and investigator/patient Global Aesthetic Improvement Scale (GAIS) scores showed progressive improvement in skin quality parameters, maintained at several months post-treatment, with low rates of mild, transient injection-site reactions.

A systematic review and meta-analysis of PDRN in wound healing found consistent acceleration of wound closure, better epithelialisation, increased vascularisation and modulation of inflammatory markers in both in vitro and in vivo models, reinforcing its regenerative potential in compromised tissues. These wound-healing data are often extrapolated to support cutaneous rejuvenation claims in aesthetic marketing, even though the study populations and endpoints are clearly different.

Overall, existing peer-reviewed data support biologically plausible regenerative effects on skin and soft tissues, but robust, blinded, head-to-head aesthetic trials with long-term follow-up remain limited.

Financial Conflicts and Limitations of the Evidence

A critical issue in interpreting the PN literature is the role of industry funding and investigator conflicts of interest. In plastic and aesthetic surgery more broadly, a 2015 analysis of three major journals found that studies with disclosed financial conflicts of interest were over seven times more likely to report positive outcomes than those without such conflicts. This does not invalidate individual results but strongly suggests systematic bias towards favourable conclusions when industry is involved.

The 2024 systematic review of PNs in aesthetic medicine explicitly notes that many available studies are small, non-randomised, and frequently linked to specific commercial products, with heterogeneous protocols and subjective outcome measures. The authors conclude that while early findings are encouraging, rigorous high-quality studies are essential to validate the effectiveness and safety of PN.

For aesthetic clinicians, this means that enthusiasm for polynucleotides should be tempered with an awareness that much of the published work is small, short-term and sometimes industry-sponsored, with limited independent replication.

What We Can Say Based on Current Evidence

• Polynucleotides, particularly PDRN and high-purity PN formulations, have a reasonably well-characterised regenerative mechanism centred on adenosine A2A receptor activation, angiogenesis, fibroblast stimulation and modulation of inflammation.
• In non-aesthetic settings (chronic wounds, ischaemic tissue), they show consistent benefits in promoting healing and tissue quality, with a good safety profile.
• Early aesthetic studies and clinical series report improvements in skin texture, elasticity, fine lines and hydration following intradermal PN treatments, with effects that build over weeks to months and limited downtime.
• The aesthetic evidence base is evolving: studies are often small, open-label, and sometimes funded or co-authored by individuals linked to manufacturers, in a field where financial conflicts are known to bias outcomes towards positive conclusions.
• Polynucleotides are positive regenerative tools with supportive data.

Sources

Squadrito F. et al. (2017) Front Pharmacol, 8:224. | Lampridou S. et al. (2025) J Cosmet Dermatol, 24(2):e16721. | Naik V. et al. (2025) International Surgery Journal, 12(4):568-574. | Lim T.S. et al. (2024) Clin Cosmet Investig Dermatol, 17:417-431. | Lopez J. et al. (2015) Plast Reconstr Surg, 136(5):690e-697e. | Pharmaceuticals (2021) 14(11):1103.