POLYNUCLEOTIDES

POLYNUCLEOTIDE POTENTIAL

DR DIANA BUZA

Dr Diana Buza combines medical expertise with an artistic eye to deliver subtle but transformative results to elevate how you feel in your own skin. She believes in working with your natural features to restore and enhance your skin’s longevity with premium, evidence-based aesthetic treatments.

DR JORDAN FAULKNER

Dr Jordan Faulkner is a full time cosmetic physician and founder of Allo Aesthetics. He is the founder and lead mentor of Unite Aesthetics Initiative and is a clinical educator at Interface Aesthetics. Dr Jordan is a brand ambassador at Revanesse and faculty member at DermaFocus. He is the co-owner of Myokine Ltd.

Polynucleotides (PNs) have emerged as one of the most discussed injectables in aesthetic medicine. Derived from fish DNA, these long chains of nucleotides are proposed to enhance skin regeneration, hydration, and elasticity through fibroblast activation and antioxidant effects.1-2Recent commentary on social media has suggested that there is no evidence supporting the use of PNs for cosmetic purposes. This type of absolutist stance feels unnecessarily polarising and, in truth, does not reflect the breadth of available data.

Our intention is not to fuel division, but to provide a measured and transparent review of the current evidence base, acknowledging both its strengths and its limitations. By critically appraising the quality of existing studies, we hope to offer clinicians a balanced and professional perspective on where PNs sit within contemporary aesthetic practice.

INTRODUCTION

Regenerative aesthetics continues to move beyond volume replacement and neuromodulation and towards modalities that support intrinsic tissue repair as practitioners increasingly turn to bio-stimulatory and regenerative agents. Polynucleotides and their smaller analogues, polydeoxyribonucleotides (PDRNs), fit within this paradigm. Structurally, PNs act as building blocks of genetic material, providing substrates for cellular repair and replication. PDRNs have been used for decades in wound-healing applications and tissue regeneration. Both PNs and PDRNs are eventually broken down into the same components and hence the evidence is often extrapolated.

Most commercially available PNs for aesthetic use are fishderived, chosen for their high purity and structural similarity to human DNA. These fragments are postulated to create a supportive scaffold in the dermis, stimulating fibroblast activity, collagen and elastin synthesis, and improving overall skin quality.1-2.

EMERGING EVIDENCE

While the precise molecular pathways continue to be explored, several biologically plausible mechanisms have been identified:

1. Fibroblast stimulation and dermal remodelling

Preclinical studies suggest that PNs may enhance fibroblast proliferation and extracellular matrix (ECM) synthesis, supporting dermal remodelling. In vitro work with PDRNs has demonstrated increased collagen types I and III production by fibroblasts, alongside improved dermal organisation. These effects are thought to be mediated, at least in part, via adenosine A2 receptor dependent signalling pathways.1.

2. Adenosine A2 receptor signalling and neovascularisation

Degradation of PNs releases adenosine, which can activate A2 A and A2 B receptors, triggering Gs protein–coupled signalling and increasing intracellular cyclic AMP. Downstream activation of protein kinase A and transcription factors such as CREB, NFkB and HIF-1may upregulate vascular endothelial growth factor (VEGF) and angiopoietin, promoting angiogenesis. Enhanced neovascularisation may improve long-term tissue perfusion, oxygenation and nutrient delivery, thereby supporting sustained dermal repair.1 That pathway is inferred from known adenosine receptor biology rather than consistently documented in skin fibroblast models and remains to be fully validated in human models. Direct evidence for PN/PDRN enhancing angiogenesis in human skin is limited as most data comes from wound-healing or ischemia models.3

3. Nucleotide salvage pathway support

PNs may also contribute to cellular regeneration through nucleotide salvage pathways. Enzymatic breakdown of DNA releases purine and pyrimidine bases, which are recycled for DNA synthesis. This process supports fibroblast proliferation and cellular repair by maintaining an adequate nucleotide pool, particularly under conditions of tissue stress or micro-injury.1

4. Hydration and water retention

PNs are moderately hydrophilic molecules capable of binding and retaining water within the extracellular matrix, which may contribute to transient dermal hydration and improved skin turgor.2 The specific biological mechanisms underlying sustained hydration benefits continues to be explored.

5. Antioxidant and free-radical scavenging

Preclinical findings suggest that PN formulations may help reduce oxidative stress by scavenging reactive oxygen species (ROS), potentially protecting against collagen degradation and photo-induced skin damage. Ongoining research aims to clarify and validate their significance in human models. Current peer-reviewed literature primarily focuses on receptor-mediated signalling and nucleotide salvage pathways rather than direct antioxidant activity.1

6. Immunomodulatory and anti-inflammatory effects

Early mechanistic studies, especially those involving PDRN, highlight the modulation of inflammatory pathways, including the downregulation of pro-inflammatory cytokines via adenosine A2 A receptor activation. This anti-inflammatory activity shows promise in supporting an improved wound-healing environment and enhanced tissue recovery.1 While these effects have been demonstrated in vitro, ongoing research is actively exploring their validation and application in human clinical settings.

THE CLINICAL PROMISE

All human trials to date investigating PNs are relatively small in scale, often non-randomised, observational, and with short follow-up durations. While these preliminary data are encouraging, they highlight the need for larger, well-designed randomised controlled trials (RCTs) to establish robust clinical efficacy and safety profiles. Mechanistic claims such as collagen stimulation, angiogenesis, gene modulation, and anti-inflammatory effects primarily derive from in vitro studies. These early findings suggest possible biological pathways but require confirmation in well-designed human clinical studies.

Mastelli et al. reported on a small prospective exploratory study in 2022 evaluating the clinical efficacy and safety of PN highly purified technology (PN-HPT), alone and in combination with hyaluronic acid, in treating moderate to severe nasolabial folds in 20 women. Over six months, the study observed significant improvements in wrinkle severity and skin texture, with no serious adverse events reported. While the findings suggest a potential synergistic effect of PN-HPT with hyaluronic acid, the study’s limited sample size and its association with a manufacturer of polynucleotide products may introduce potential bias. Larger, independent studies are warranted to confirm these.4

A randomised, double-blind, split-face clinical trial by Ye Jin Lee et al in 2022 evaluated the comparative efficacy and safety of PN injections versus hyaluronic acid (HA) fillers for periocular rejuvenation. The study demonstrated that both treatments led to statistically significant improvements. However, PN-treated sides showed superior improvements in skin quality, while HA fillers provided more immediate volumising effects. PN injections were associated with a more natural appearance and fewer adverse effects. Patient satisfaction scores were high for both modalities, but PN treatment was favoured for long-term skin revitalisation rather than volume correction. Overall, the authors concluded that polynucleotides represent a safe and effective alternative to hyaluronic acid fillers for periocular rejuvenation, particularly for skin quality rather than volumisation.5

In 2024, Lee et al provided a thorough and insightful review of human studies, exploring PNs in aesthetic medicine.6 Their analysis highlighted encouraging evidence for improvements in skin texture, wrinkle depth, hydration and elasticity across multiple clinical trials. Although variability existed in study designs and outcome measures, the overall findings support the potential of PNs to contribute to skin rejuvenation. The authors call for more rigorous, standardized clinical trials lasting for longer durations to clarify the efficacy and mechanisms of polynucleotides in aesthetic applications.

Lampridou et al performed a systematic review of nine small studies totalling 219 participants in 2025, focusing specifically on PNs for facial rejuvenation.7 The review reported consistent findings of improved wrinkles, skin elasticity, and texture, accompanied by high patient satisfaction and minimal adverse events. Despite these promising outcomes, the authors rated the overall quality of evidence as low to moderate due to common limitations such as small sample sizes, lack of randomisation, and short follow-up periods. The heterogeneity in study protocols and endpoints further complicates definitive conclusions.

These encouraging data reflect significant practitioner interest and positive patient experiences, however, it is important to interpret these results within the context of methodological constraints and the need for further high-quality randomised evidence.

THE CRITICAL VIEW

The perception of a large evidence gap arises primarily from:

• Small sample sizes

• Short follow-up periods

• Heterogeneity in product formulations, dosing and techniques

• Limited use of validated objective endpoints

These factors reflect the novelty of PNs in aesthetics rather than a failure of the modality itself. Current reviews note that larger placebo-controlled randomised trials are still required. Long-term durability data remain limited beyond six to 12 months and comparisons with established treatments have not yet been conducted.

These gaps highlight the importance of continued research, not a dismissal of existing findings. Importantly, no review so far suggests that PNs are ineffective, only that more robust evidence is required to quantify their impact with precision.

SAFETY PROFILE

Published studies consistently describe PNs as well tolerated, with transient redness, swelling or bruising as the most common side effects. In clinical studies of PN-HPT, no serious adverse events were reported.4 However, long-term safety data remain scarce, especially beyond 12 months.2,4,5,

DISCUSSION

The rapid evolution of regenerative aesthetics means that clinical adoption often precedes large-scale research. This is not unique to PNs; it is a familiar pattern seen with many now-established aesthetic treatments.

High-quality RCTs are essential, not only to determine efficacy but also to refine dosing, injection technique and treatment intervals. Without standardised endpoints, for example histological collagen quantification or validated elasticity measures, outcomes remain subjective.

As with many innovations in aesthetic medicine, the role of PNs will be further cemented through the development of well-designed RCTs and standardised outcome measures. In the interim, they can be responsibly presented to patients as a promising adjunctive treatment supported by encouraging anecdotal evidence from clinical practice, highlighting their potential benefits in positive ageing with strong clinical momentum. The verdict, therefore, is not finalised but advancing, with a clear opportunity for the specialty to build the high-quality evidence base.

CONCLUSION

Polynucleotides stand as a compelling and increasingly adopted option within regenerative aesthetics, supported by biologically plausible mechanisms and a favourable safety profile. Early clinical data, alongside extensive real-world practitioner experience, consistently point towards improvements in skin quality, hydration and overall dermal vitality6,7 . Although the current body of clinical research is limited in scale, the largely positive and reproducible findings should be viewed as indicative of an emerging therapy.

While it is universally accepted that higher-quality, robust clinical trials are still required, the absence of large RCTs should not be conflated with an absence of evidence altogether. The literature is steadily expanding, and we now have systematic reviews and meta-analytical data concluding that polynucleotides do confer measurable aesthetic benefits. As with many emerging therapies in aesthetic medicine, the accumulation of rigorous evidence is incremental and unfolds over years rather than months.

Equally important is an appreciation of the hierarchy of scientific evidence. Alongside preclinical studies and early human trials sit expert clinical opinion, which, although classified as lower-level evidence, remains a recognised and legitimate component of evidence-based medicine. The widespread adoption of PNs by clinicians working full time in cosmetic practice, coupled with consistently high levels of patient and practitioner satisfaction, represents a substantial body of experiential data. As the evidence base continues to mature, such real-world insights help guide responsible clinical use and underscore that the current conversation is not about “no evidence”, but about evidence that is actively developing.

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