Degenerative meniscal tears are a common cause of knee pain and functional limitation, particularly in middle-aged and older adults. Conservative management remains the first-line treatment, with increasing interest in injectable therapies aimed at symptom relief and tissue preservation. Polynucleotide (PN)-based injectables have shown potential benefits in knee osteoarthritis; however, their role in degenerative meniscal pathology remains unclear. This scoping review aimed to map and synthesise the current clinical evidence on the efficacy and safety of PN injections in adults with degenerative meniscal tears and to identify gaps in the literature. A scoping review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines. Electronic databases, including MEDLINE (Ovid and EBSCO), PubMed, ScienceDirect, SAGE Journals, Wiley Online Library, and the Cochrane Library, were searched from inception to January 2026. Eligible studies were human clinical investigations involving adults with degenerative, non-traumatic meniscal tears treated with PN-based injections and reporting clinical or radiological outcomes. Study selection, data extraction, and risk-of-bias assessment were performed descriptively. The search identified 72 records, of which 20 full-text articles were assessed for eligibility. One prospective clinical study involving 30 patients met the inclusion criteria. Intra- and perimeniscal PN injections were associated with improvements in pain and functional outcomes, as measured by validated patient-reported outcome scores, including the Visual Analogue Scale, Knee Injury and Osteoarthritis Outcome Score, International Knee Documentation Committee score, and Tegner Activity Scale. No serious treatment-related adverse events were reported. Given the limited number and heterogeneity of eligible studies, quantitative synthesis was not undertaken. Current evidence on PN injections for degenerative meniscal tears is limited but suggests potential symptomatic benefit and a favourable safety profile. High-quality randomized controlled trials are required to better define the efficacy, comparative effectiveness, and clinical role of this emerging treatment.

Objectives: Horizontal ridge augmentation remains a clinical challenge due to limitations in terms of spatial maintenance, graft stability and predictability of new bone formation. The umbrella-screw tent technique provides mechanical stability for particulate grafts, while adjuvants such as hyaluronic acid (HA) and polynucleotides (PN) may enhance biological remodeling. Evidence for this compound in implant-related bone augmentation is still scarce. Material and methods: In a single patient with a knife-edge alveolar ridge, augmentation was performed in regions 34 to 36 using the umbrella-screw tent technique. The defect was grafted with deproteinized bovine bone mineral (DBBM) mixed with hyaluronic acid (HA) and polynucleotides (PN), supplemented with platelet-rich fibrin (PFR) and covered with a resorbable collagen membrane. After six months, two implants were installed, and a biopsy was obtained by trepanation for histological and histomorphometric analysis. Results: Healing occurred without compromise, with no signs of infection or graft exposure. Horizontal bone gain averaged 4.5 mm, corresponding to a relative Target Performance Index (TPI-h) of 75%. Histomorphometric analysis revealed a total mineralized fraction of 76.4%, consisting of 36.1% newly formed bone and 40.3% residual DBBM particles. The xenogeneic granules were completely integrated into mature bone, with no signs of inflammation or foreign body reaction. Conclusion: The case report illustrates that the combination of DBBM with HA and PN, stabilized by the umbrella-screw tent technique, can lead to significant new bone formation and favorable graft integration. Although limited by its single-case design, the case report provides preliminary insights into the synergistic potential of HA and PN as biological enhancers in bone augmentation, warranting further controlled studies.

This study explores an alternative method of delivering polynucleotides (PNs) using a transdermal drug delivery device instead of traditional injection methods. These devices can deliver PNs in a noncontact manner and may offer several advantages over traditional injection techniques, including reduced pain and faster recovery time. A clinical trial was conducted to compare the effectiveness of PN injections and transdermal drug delivery devices in 4 participants. Each participant received 3 treatments using the injection method on one side of the face and the transdermal drug delivery device on the other. The right hemiface was treated with cryogenic transdermal delivery (TargetCool), and the left hemiface was treated with manual intradermal injection. Outcomes were assessed through standardized photography and skin analysis, and participant satisfaction was examined using the Global Aesthetic Improvement Scale and visual analog scale. Treatment with the transdermal drug delivery device showed similar skin improvement to PN injection, with the advantage of less pain and a shorter recovery time. Skin density measurements using ultrasound showed that both methods were effective, but the transdermal drug delivery device provided slightly better skin density improvement in some cases. Transdermal drug delivery devices are a safe and effective alternative to traditional PN injections, with similar skin improvement outcomes.

Ultraviolet A (UVA) radiation, a principal driver of skin photoaging, generates excessive reactive oxygen species (ROS) in dermal fibroblasts, causing oxidative stress, loss of viability, inflammatory signaling, and extracellular matrix (ECM) degradation. Hyaluronic acid (HA) and polynucleotides (PN) are clinically used dermal biomaterials; however, their protection against UVA injury remains insufficiently defined. We evaluated HA, PN, and their combination in human dermal fibroblasts (HDFs) subjected to photodamage. HDFs were pretreated with HA, PN, or both, irradiated with 20J/cm2 UVA, and then maintained in treated media to mimic therapeutic recovery. UVA reduced viability and proliferation, downregulated ECM genes (COL1A1, FN1), and increased intracellular and mitochondrial ROS and proinflammatory cytokine gene (TNF-α). Monotherapy partially alleviated these changes. In contrast, combined HA + PN synergistically improved survival and proliferation, lowered ROS to near baseline, restored ECM transcription, and upregulated antioxidant enzymes (GPX1, SOD2). HA + PN also increased fibroblast invasion, indicating regenerative activity beyond cytoprotective effects. Under basal conditions, neither HA nor PN showed cytotoxicity or prooxidant effects, while modestly enhancing ECM transcription. These findings demonstrate that HA and PN act synergistically to counter UVA-induced oxidative stress and support dermal regeneration, highlighting a combinatorial bioactive strategy for photoaged skin.

Background/Objectives: Intra-articular polynucleotide (PN) has emerged as an alternative to hyaluronic acid (HA) for treating knee osteoarthritis (OA), with randomized controlled trials (RCTs) reporting similar or greater pain reduction. Real-world evidence on both single- and repeated-cycle outcomes remains limited. This study evaluated PN's real-world effectiveness and safety and whether its pain reduction falls within ranges reported in previous PN-HA RCTs, and evaluated repeated-cycle outcomes. Methods: Clinical data from 1048 PN-treated OA patients were retrospectively reviewed. The safety set comprised 1024 patients with follow-up visits. The efficacy set included 975 patients who completed 3-5 weekly PN injections with evaluable VAS, CGI, and PGI data at baseline, 3, and 6 months. A repeated-treatment subgroup (n = 45) received a second PN cycle 6 months later. First-cycle outcomes were compared with PN-HA RCTs. Results: In the first-cycle (n = 975), VAS decreased from 50.30 mm to 23.02 and 22.43 mm at 3 and 6 months (-27.28 and -27.87 mm; p < 0.0001), showing a comparable magnitude to RCT-reported ranges (~27-41 mm). CGI improvement was 81.0% and 79.6%, and PGI improvement 78.8% and 78.1% at 3 and 6 months. In the repeated-treatment subgroup (n = 45), despite a lower second-cycle baseline VAS of 31.00 mm (vs. 50.30 mm at first-cycle baseline), VAS decreased to 14.07 mm and 17.33 mm at 3 and 6 months (-16.93 and -13.67 mm; p < 0.001), achieving comparable absolute post-treatment pain levels. Among 1024 patients, three mild-to-moderate arthralgia events (0.29%) occurred, with no serious device-related adverse events in either cycle. Conclusions: PN provided meaningful 6-month pain reduction in a comparable magnitude to previous RCTs and showed consistent benefit with repeated administration without new safety concerns.

Polynucleotides (PNs) and polydeoxyribonucleotides (PDRNs) have gained immense traction in aesthetic medicine due to their regenerative properties. These biostimulator agents act at a cellular level to promote fibroblast proliferation, angiogenesis, extracellular matrix remodelling, and DNA repair – enhancing skin elasticity, hydration and overall tissue quality. Clinically, PNs have been used in multiple different indications, including facial rejuvenation (periorbital, perioral, midface), neck and décolletage laxity, hand revitalisation, hair restoration, acne scarring and post-inflammatory pigmentation. Although current evidence is limited to small-scale studies of low-moderate methodological quality, outcomes consistently report skin texture enhancement, wrinkle reduction, improved dermal hydration, and high patient satisfaction, with only mild and transient side effects observed. This review analyses available literature, positioning PNs as a safe, effective and distinctly regenerative option distinguishing them from traditional skin boosters and other biostimulators.

The aesthetics industry is undergoing a paradigm shift toward regenerative and biologically based therapies. This article critically compares polynucleotides (PNs) and exosomes, two innovative modalities demonstrating significant potential in aesthetic and dermatologic applications. Polynucleotides, composed of nucleotide polymers, promote fibroblast proliferation, collagen synthesis, and cutaneous hydration, contributing to skin repair and rejuvenation. Exosomes, nanoscale extracellular vesicles derived from stem cells, facilitate intercellular communication and deliver bioactive molecules that enhance tissue regeneration, immune modulation, and wound healing. While both therapies exhibit promising clinical outcomes, exosomes provide a broader regenerative mechanism but face greater regulatory and ethical scrutiny due to their origin and production methods. The article underscores the necessity for evidence-based practice, safety evaluation, and standardised protocols in advancing these emerging biotechnologies within aesthetic medicine.

ABSTRACTBackgroundAtopic dermatitis (AD) is a chronic inflammatory skin disease characterized by persistent itching, dryness, redness, and recurrent eczematous lesions, significantly impacting patients' quality of life and psychological well‐being. Despite various effective conventional treatments, innovative therapeutic approaches that simultaneously provide anti‐inflammatory effects and enhanced skin hydration remain essential.ObjectiveThis case‐series study aimed to evaluate the clinical efficacy, patient satisfaction, and safety profile of polynucleotide (PN)‐based injectable therapies in patients with AD.MethodsPatients with clinically diagnosed AD underwent intradermal injections of PN. Treatment outcomes were assessed by comparing standardized clinical photographs taken before and after the PN treatment, focusing on improvements in erythema, skin thickness, and overall skin hydration. Additionally, patient‐reported outcomes, including reductions in itching, discomfort, and treatment satisfaction, were evaluated.ResultsPosttreatment evaluations demonstrated notable clinical improvements, including reduced erythema, decreased skin thickness, and enhanced skin hydration and elasticity. Patients consistently reported significant alleviation of itching and overall discomfort. Furthermore, high patient satisfaction and good adherence to treatment were observed, with no significant adverse events or side effects reported.ConclusionThis exploratory case series provides preliminary observations suggesting that PN‐based injectable therapies may offer benefits for patients with AD, particularly in improving skin hydration, barrier function, and symptomatic relief. While positive outcomes were documented in all four cases, the absence of validated scoring systems, objective biophysical measures, long‐term follow‐up, and a control group limits the strength and generalizability of these findings. PN injections in this context remain off‐label, and further prospective, controlled studies with larger, more diverse populations are essential to establish efficacy, safety, optimal dosing regimens, and durability of response.

Polynucleotides (PN) are innovative polymers that improve skin hydration and elasticity, serving as alternatives to traditional dermal fillers. Medical devices based on PN High Purification Technology (PN HPT) represent a new generation of injectable products designed to restore hydration, elasticity, and overall tissue quality. PN HPT is known for its clinical versatility and excellent tolerability. To assess the real-world performance and safety of Plinest (40 mg/2 mL of PN HPT in a 2 mL pre-filled syringe), a CE-marked class III medical device for skin rejuvenation of the face, neck, and décolleté. This observational clinical data collection involved 66 adult patients, each of whom could receive treatment in up to three areas (face, neck, décolleté). Patients underwent three sessions of intradermal PN HPT injections. A total of 106 questionnaires were collected: 47 for the face, 33 for the neck, and 26 for the décolleté. Performance was evaluated using the Global Clinical Improvement Scale (GCI-S) and Global Aesthetic Improvement Scale (GAIS). Safety was monitored through spontaneous adverse event (AE) reporting. Clinician-reported outcomes showed visible improvement in 100% of facial treatments, with 53.5% rated as "marked" or "excellent." In the neck and décolleté areas, moderate to significant improvements were observed in over 93% and 88% of cases, respectively. Patient satisfaction ranged from 97% to 100%. No serious AEs occurred. PN HPT demonstrated a favorable tolerability and performance profile in real-life aesthetic practice, supporting its role in improving skin quality and reducing signs of aging.

Abstract: Polynucleotides (PNs) are increasingly used in aesthetic dermatology, supported by emerging clinical evidence and growing interest in restorative approaches to skin treatment aiming to improve skin conditions. This expert opinion article brings perspectives from an international panel of dermatologists and aesthetic physicians on the use of PNs (Rejuran ® , PharmaResearch, South Korea) across dermatological indications. The proposed mechanism of action of PNs involves the formation of a hydrophilic, scaffold-like matrix that may support tissue remodeling and hydration. This article highlights the clinical applications of PNs across four indications: skin hydration and rejuvenation; structural support through deep-plane injections; barrier repair in rosacea and eczema; and scar remodeling. For each, the authors provide suggested treatment protocols based on real-world use, including guidance on injection techniques and anatomical targets. PNs have demonstrated a favorable safety profile, with no reported cases of granuloma or vascular occlusion in the literature to date. Their biocompatibility and tolerability make them a promising option, particularly for sensitive or barrier-compromised skin. However, the current evidence base remains limited, and further studies, including randomized trials and histological validation, are needed. This article provides practical clinical guidance while highlighting areas for future research and standardization in the aesthetic use of PNs. Keywords: polynucleotides, skin rejuvenation, ligament strengthening, skin structural support, scar remodeling

Postoperative pain, swelling, and transient trismus commonly follow impacted mandibular third-molar surgery. Hyaluronic acid (HA) can modulate early inflammation and support soft-tissue repair, while polynucleotides (PN) may further enhance fibroblast activity. This study evaluated whether an intrasocket PN-HA gel improves early postoperative outcomes versus standard care. Single-center, retrospective split-mouth study in adults undergoing bilateral removal of partially impacted mandibular third molars. One socket received PN-HA gel (Regenfast © , 5mL) before suturing (TG), the contralateral socket received no adjunct (CG). Outcomes: pain (VAS 0-10) at 12 hours and daily for 7 days; maximum interincisal distance on 2, 5, and 7 postoperative days (POD); facial swelling from standardized 3D facial scans at baseline, POD2, POD5, and POD7. Parametric analyses used paired tests and one-way ANOVA with Tukey post hoc; Pearson correlations assessed relations among pain, swelling, and mouth opening. Eighteen patients completed follow-up without complications. Operative time was comparable between allocations. Pain peaked at approximately 12 hours and was lower on test sides during the early window, with differences diminishing by POD5-7. Swelling increases were smaller on test sides at POD2 and POD5 and converged by POD7. MID recovered faster on test sides at POD2 and POD5, approaching baseline in both groups by POD7. Correlations reflected expected dynamics: higher pain was associated with greater swelling and reduced mouth opening, most pronounced around the inflammatory peak. Intrasocket PN-HA gel reduced early pain and swelling and hastened mouth-opening recovery (greatest at 48-72h, converging by 1week), indicating clinical utility for reducing short-term morbidity after third-molar surgery.

Polynucleotide (PN) fillers are widely used for skin rejuvenation due to their regenerative properties; however, injection-related pain remains a major drawback. This randomized, patient-blinded, split-face study evaluated a novel "ionization-adjusted" PN filler with modified pH and ionic strength designed to reduce injection pain without compromising efficacy. Fifteen participants received 1mL of conventional PN filler on one side of the face and 1 mL of the ionized PN filler on the other. Pain was assessed using a 10-point Visual Analog Scale (VAS), while wrinkle improvement was evaluated using the Crow's Feet Grading Scale (CFGS) and Global Aesthetic Improvement Scale (GAIS). The ionized PN filler demonstrated significantly lower pain scores (VAS 3.39 ± 1.81) compared to the conventional filler (VAS 5.04 ± 2.19, p < 0.005), with fewer cases of erythema (40% vs. 60%) and embossing (13.3% vs. 56.7%). Both formulations showed significant improvements in CFGS and GAIS scores without statistical differences. These findings suggest that ionization-adjusted PN filler provides a more comfortable injection experience while maintaining similar clinical efficacy and safety profiles. LEVEL OF EVIDENCE I: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Background/Objectives: Sodium polynucleotide (PN) injection has recently been considered as a potential intra-articular therapy for knee osteoarthritis (OA); however, there is limited evidence regarding the long-term consistency of repeated PN cycles. To evaluate the clinical effectiveness of repeated intra-articular PN injections after the initial 6 months of therapy in patients with knee OA, using nationwide claims data. Methods: We conducted a retrospective cohort study using data from the Korea Health Insurance Review and Assessment Service collected between 2020 and 2023. Patients who received PN injections for knee OA were classified into two groups based on the treatment cycle: Group 1 (single cycle) and Group 2 (re-administration). Surgical outcomes and symptomatic indicators, including pain-related hospital visits, arthrocentesis, nonsteroidal anti-inflammatory drug prescriptions, and antidepressant prescriptions, were analyzed. Results: A total of 142,322 patients were included in this study. Readministration of PN was associated with significantly lower rates of total knee arthroplasty (2.31% vs. 4.92%, p < 0.0001) and delayed time to surgery (252.0 vs. 176.6 days, p < 0.0001). Similar trends were observed for hemiarthroplasty, with a lower incidence (0.28% vs. 0.55%, p < 0.0001) and longer time to surgery (240.7 vs. 162.2 days, p < 0.0001) in the readministration group. All groups showed a timewise reduction in pain-related hospital visits and instances of arthrocentesis. Safety outcomes were not assessed in this claim-based dataset. Conclusions: Repeated cycles of PN injections provide sustained clinical benefits and may effectively delay the need for surgical intervention in patients with knee OA, supporting their possible role as a long-term conservative treatment option. Radiographic severity and safety outcomes were unavailable in this claims dataset, limiting the adjustment for baseline OA severity and restricting causal interpretation.

Polydeoxyribonucleotides (PDRNs) and polynucleotides (PNs) are biologically active DNA-derived polymers with emerging applications in regenerative dentistry. Acting through adenosine A2A receptor activation and modulation of inflammatory responses, these biomolecules promote angiogenesis, enhance fibroblast proliferation, and stimulate extracellular matrix synthesis. In periodontal therapy, their potential to accelerate healing, reduce inflammation, and support the regeneration of gingival connective tissue, periodontal ligament, cementum, and alveolar bone is of increasing clinical interest. This review synthesizes current preclinical and clinical evidence regarding the use of PDRNs and PNs for tissue regeneration in dentistry, including their mechanisms of action, delivery strategies, synergistic effects with biomaterials and growth factors, and safety profile. Furthermore, recent advances in injectable formulations, scaffold integration, and combined therapies are discussed. The review also highlights gaps in evidence, methodological limitations in existing studies, and future research directions needed to establish standardized treatment protocols. A total of 21 studies (10 PDRNs and 11 PNs/ODNs) were analyzed. PDRNs and PNs consistently demonstrated preclinical regenerative efficacy, although robust clinical validation remains limited.

Viscosupplementation is a widely used treatment for osteoarthritis, aiming to restore the viscoelastic properties of synovial fluid and improve joint function. While hyaluronic acid (HA), BDDE-crosslinked hyaluronic acid (BDDE-HA), and polynucleotide (PN) have been studied individually, the rheological properties of their mixtures remain insufficiently explored. This study investigates the viscoelastic characteristics of PN/HA and PN/BDDE-HA blends through rheological evaluations, including simple shear tests, oscillatory shear tests, and 3-interval thixotropy tests. Results indicate that BDDE-HA maintains high viscosity over a range of shear rates, whereas PN exhibits viscosity loss at high shear rates. PN/HA exhibits synergistic structural recovery properties, consistent with clinical findings suggesting improved efficacy compared to individual components. PN/BDDE-HA exhibits improved viscoelastic behavior but prolonged structural recovery. These findings highlight the importance of comprehensive rheological analysis in understanding viscosupplement formulations and their potential clinical implications. This study provides fundamental data to support future clinical research on PN/BDDE-HA as a novel viscosupplement.

Background: Tendons are among the most frequently affected structures in musculoskeletal disorders. Polynucleotides (PNs) have been proposed to promote tendon regeneration by enhancing collagen synthesis and reducing inflammation. This retrospective clinical study aimed to evaluate the clinical effects of PNs injections in patients with different kinds of tendinopathy (mostly gluteal tendinopathy, biceps brachii tendinopathy and Achilles tendinopathy), focusing on pain reduction and functional improvement. Methods: Sixty-eight patients with clinically diagnosed tendinopathy received three peritendinous injections of a PNs-based medical device at baseline (T0), two weeks (follow-up 1), and four weeks (follow-up 2) post-T0. Follow-up assessments were conducted at follow-up 1, follow-up 2-, eight- and 24-weeks post-follow-up 2. The primary outcome was pain reduction measured by the numerical rating scale (NRS). Secondary outcomes included pain-related functional limitation (VAS-function), the Clinical Global Impression-Improvement scale, and patient satisfaction on a 5-point Likert scale. Results: A mean NRS and VAS-function reduction of, respectively, -1.76 ± 0.08 and -1.74 ± 0.07 were found per follow-up, with statistically significant improvements over time. At the final follow-up, 88% of patients reported being "satisfied" or "very satisfied" with the treatment. Conclusions: The results support the efficacy and safety of PNs treatment in patients with tendinopathies, as it led to significant improvements in pain and function. Further high-quality clinical studies are needed to validate these findings.

Biomimetics offers promising tools to improve wound healing in difficult clinical conditions. Polynucleotides (PN) show high potential for tissue repair in oral and periodontal surgery, by relying on the body's inherent self-healing capabilities. The aim of the present study was to elucidate in vitro the effects of Odonto-PN (O-PN) and Regenfast (REG), two PN-based compounds, on oral tissue repair. We employed 3D spheroid cultures and cell scratch assays to simulate wound healing in vitro, assessing cell migration and morphology under normal conditions and following mitomycin-induced inhibition of cell growth. Both O-PN and REG supported early cell viability and spheroid disassembly. O-PN supported the initial outgrowth of fibroblasts, whereas REG enhanced sustained cell migration at later time points. In scratch assays, REG effectively facilitated defect closure - even under mitomycin treatment - and induced a more elongated, migratory cell phenotype. These findings suggest that both O-PN and REG can favorably modulate fibroblast function to support wound repair. While O-PN fosters early activation and cell viability, REG exerts potent pro-migratory effects that may be particularly useful for complex periodontal regeneration. Their selective use could provide valuable adjuncts in clinical protocols aimed at restoring delicate oral structures, such as the interdental papillae.

Background:Automated injection devices are becoming essential tools in aesthetic medicine, offering precision and consistency in treatments such as polynucleotide (PN) injections for skin rejuvenation. This study aimed to analyze the dermal thickness across facial regions and evaluate the consistency of injection depth achieved with the Rejumate automatic injector.Methods:A total of 31 patients (average age 48.2 y; 4 men and 27 women) underwent dermal thickness measurements using high-resolution 33-MHz ultrasound in 11 facial regions, including the forehead, temple, orbital rim, lower eyelid, malar, anterior cheek, lateral cheek, posterior cheek, jawline, and chin. Each patient then received a standardized 2-mL PN injection using the Rejumate injector with a 0.8-mm needle across 317 individual points. Injection depth, distribution, and consistency were measured and analyzed.Results:The average dermal thickness across regions ranged from 0.53 (lower eyelid) to 1.18 mm (temple and posterior cheek). The Rejumate injector demonstrated a high degree of consistency, achieving an average injection depth of 0.55 mm (SD = 0.13 mm), with a median depth of 0.54 mm. The depth range (0.29–0.99 mm) and interquartile range (0.17 mm) indicated controlled depth with minimal variability.Conclusions:The Rejumate automatic injector reliably delivers PN at a controlled depth, showing minimal variability across injections. This precision supports improved safety and efficacy in PN delivery, providing a valuable reference for clinical application in aesthetic treatments. Given the anatomical differences in dermal thickness across facial regions, this standardized approach may optimize outcomes and increase patient satisfaction.

Polynucleotide (PN), a high-molecular-weight DNA fragment derived from salmon and other fish sources, shows promising anti-aging and regenerative effects on the skin. This study investigated how PN enhances collagen synthesis, focusing on its effect on phosphoenolpyruvate carboxykinase 1 (PCK1) in senescent macrophages and its downstream effects on fibroblasts. Using in vitro senescent cell models and in vivo aged animal models, PN significantly upregulated the adenosine 2A receptor (A2AR), adenylate cyclase (AC), cyclic AMP (cAMP), protein kinase A (PKA), and cAMP response element-binding protein (CREB) in senescent macrophages. This led to increased PCK1 expression, which reduced oxidative stress and promoted M2 macrophage polarization, associated with elevated levels of interleukin-10 and tumor growth factor-β. Conditioned media from PN-treated macrophages enhanced SMAD family member 2 and signal transducer and activator of transcription 3 phosphorylation in senescent fibroblasts, increasing collagen I and III synthesis and reducing nuclear factor-κB activity. In vivo, PN administration elevated expression of the A2AR/AC/PKA/CREB/PCK1 pathway, reduced oxidative stress, increased M2 macrophage markers, and significantly improved collagen density and skin elasticity over time. Use of a PCK1 inhibitor attenuated these effects, highlighting the pivotal role of PCK1. Overall, PN modulates macrophage-fibroblast interactions via the CREB/PCK1 axis, enhancing collagen synthesis and counteracting age-related skin changes. PN has emerged as a promising therapeutic agent for skin rejuvenation by targeting cellular senescence and promoting extracellular matrix restoration.

Polynucleotide (PN) and polydeoxyribonucleotide (PDRN) are DNA-derived biopolymers increasingly recognized for their potential in dermatology. Despite their structural similarities, PN and PDRN exhibit distinct functions due to differences in polymer length and molecular weight. PN, composed of longer DNA fragments, plays a key role in extracellular matrix remodeling. Conversely, PDRN, composed of relatively shorter oligonucleotide sequences than those of PN, enhances skin condition through adenosine receptor activations and supports nucleotide synthesis via both the salvage and de novo pathways. This review provides a critical comparison of the molecular characteristics and functions of PN and PDRN with particular emphasis on their dermatological applications. By delineating their respective roles in esthetic and regenerative medicine, we aim to highlight recent advances that may guide the development of optimized treatment strategies and foster evidence-based clinical practice.