As previously mentioned and shown in Fig. 1 herein, PDRN is degraded by extracellular ectonucleases (CD39 and CD73) into nucleosides, predominantly adenosine [4]. The elevated adenosine binds to A2AR on endothelial cells, fibroblasts, and immune cells [8], activating Gₛ‑protein–coupled adenylate cyclase and increasing intracellular cAMP levels. This triggers protein kinase A signaling, which upregulates hypoxia‑inducible factor‑1 and cAMP response element-binding protein while inhibiting nuclear factor kappa‑light‑chain‑enhancer of activated B cells, thereby shifting the tissue milieu toward anti‑inflammatory and pro‑angiogenic states: VEGF and angiopoietins are upregulated [12,13], whereas the pro‑inflammatory cytokines (tumor necrosis factor‑alpha, interleukin‑6 [IL‑6], and high‑mobility group box‑1) are suppressed and the anti‑inflammatory cytokine IL‑10 is enhanced. In rodent models of inflammatory arthritis, the reduction of joint inflammation and cartilage damage by PDRN is reversed by A2AR antagonists, confirming receptor-mediated immunomodulation [14,15]. Furthermore, A2AR signaling promotes tissue regeneration by enhancing fibroblast proliferation, collagen synthesis, and migration; stimulating endothelial cell proliferation and neovessel formation; and activating osteoblast and chondrocyte functions. In vitro, PDRN increases human osteoblast proliferation and alkaline phosphatase activity—markers of bone formation—and augments aggrecan and type II collagen deposition in chondrocytes while reducing matrix metalloproteinase‑2 (MMP‑2) and MMP‑9 activities [16,17]. These combined actions limit apoptosis, reduce inflammatory stress, and prepare the injured tissues for effective repair.

A unique aspect of PDRN is its role in providing building blocks for DNA synthesis in healing cells. Under conditions of tissue injury, especially hypoxia or nutrient deprivation, cells often cannot efficiently synthesize de novo nucleotides. Instead, they rely on salvage pathways to recycle nucleotides for DNA repair and replication [4]. PDRN, a DNA polymer, is a direct source of purines and pyrimidines when broken down [1]. Experimental studies have demonstrated that radiolabeled PDRN fragments are taken up by proliferating fibroblasts and are incorporated into the DNA of dividing cells, indicating that PDRN supplies nucleotides for DNA synthesis. By enhancing the salvage pathway, PDRN accelerates the proliferation of cells required for tissue regeneration [18]. This mechanism complements A2AR activation, while adenosine signaling provides pro-growth and pro-angiogenic signals. The salvage pathway ensures that cells have the raw materials to respond to those signals by synthesizing DNA and dividing. This results in an overall increase in wound closure and tissue repair. For instance, the activation of the salvage pathway via PDRN has been linked to faster re-epithelialization in skin wounds. This may increase granulation tissue formation in PDRN-treated ulcers [19].

Through pathways, PDRN influences multiple aspects of wound healing. It stimulates the release of growth factors such as fibroblast growth factor, insulin-like growth factor, and epidermal growth factor indirectly via A2AR-mediated signaling [20], which in turn encourages fibroblast migration and differentiation into myofibroblasts for wound contraction. It promotes endothelial cell proliferation and new vessel sprouting (angiogenesis) to supply the regenerating tissues. It also appears to protect cells from stress-induced damage; for example, treating human dermal fibroblasts with PDRN after ultraviolet B irradiation led to activation of p53 and enhanced DNA repair, suggesting potential anti‑photoaging benefits [21]. Additionally, PDRN may aid adipose tissue-derived stem cell niches, as one study noted the increased proliferation of preadipocytes with PDRN exposure, potentially expanding the pool of progenitor cells available for repair [22,23]. All of these effects converge to create a more regenerative environment. The “dual action” of PDRN via cell signaling and substrate provision is thought to underlie the improved healing outcomes observed in experimental models. In diabetic murine models of impaired wound healing, PDRN treatment restored normal wound closure rates with histological evidence of higher vascular density and better-organized collagen deposition relative to untreated controls [24]. These benefits were largely lost when an A2AR antagonist was co-administered, underscoring the centrality of this receptor in the effects of PDRN.

In summary, PDRN’s mechanism of action are mainly twofold: it not only activates pro-healing signaling via A2AR stimulation, leading to angiogenesis and reduced inflammation, but also supplies the necessary nucleotides for cell proliferation through the salvage pathway. This combination results in accelerated and effective tissue regeneration across various cell types (endothelial cells, fibroblasts, keratinocytes, and osteoblasts), which explains its broad utility in regenerative medicine and wound management.

A critical aspect of any therapeutic agent, especially a biological agent such as PDRN, is its safety profile. PDRN has consistently demonstrated excellent safety and tolerability in both preclinical and clinical studies. This section summarizes findings on PDRN’s adverse effects, or lack thereof, and discusses any precautions.

PDRN has shown no significant toxicity in animal studies, even at high doses. Acute and chronic toxicity tests in rodents revealed that repeated systemic administration of PDRN did not cause organ damage or mortality [37]. For example, Galeano et al. [38] reported that PDRN at a dose of 8 mg/kg (a dose much higher on a weight basis than typical human doses) showed no toxic effects on mice’s brain, liver, lungs, muscle, or heart on histological examination. Similarly, long-term administration did not induce blood test or organ function abnormalities. These findings are attributed to the nature of PDRN as a polymer of nucleotides, which are normal cellular constituents. Once broken down, its metabolites can be integrated or excreted without causing harm. Furthermore, as the extraction process removes proteins, the risk of immune reactions (such as anaphylaxis or serum sickness) is minimal [39].

Human trials on PDRN have uniformly reported a low incidence of adverse events. In a large diabetic foot ulcer trial (216 patients), there were no differences in adverse effects between the PDRN and placebo groups over 8 weeks [25]. The investigators noted excellent safety and tolerability with no systemic side effects or wound complications attributable to PDRN [25]. Injection-site reactions are rare and mild. Similarly, trials on pressure and venous ulcers have not reported any significant adverse outcomes of PDRN injections or topical application [26]. In osteoarthritis studies, intra-articular PDRN was as safe as HA injections. A meta-analysis found no significant difference in adverse event rates (and overall very low event numbers in both groups) [40]. Some patients experience transient injection-related pain or swelling, which is common with any joint injection; however, there have been no reports of inflammatory flares or joint infections attributable to PDRN. Even when PDRN was combined with other substances (such as HA or used in a gel with HA), no new safety issues emerged [41].

Immune reactions are a theoretical concern for biological agents derived from animal sources. However, the manufacturing of PDRN yields highly pure DNA fragments, removes immunogenic proteins, and produces a product that is not associated with allergic reactions. Antibody formation against PDRN or diminishing efficacy with repeated use has also been not reported. Clinical practice in chronic conditions often involves repeated courses of PDRN (e.g., serial injections for chronic ulcers or a series of joint injections over months), and no loss of efficacy or adverse immune events have been observed. The origin of DNA from fish sperm raises the question as to whether patients with fish allergies are at risk. Nevertheless, because proteins are the usual allergens and PDRN contains negligible amounts of protein, it is generally considered safe even in these individuals, although caution and monitoring are prudent. No cases of allergic anaphylaxis due to PDRN have been documented in the literature.

The adverse effect profile of PDRN is immature. No significant side effects have been consistently noted across clinical trials and no dose-limiting toxicities have been identified. Mild effects that have been observed infrequently include transient pain at the injection sites, minor bruising, and mild redness when injected intradermally (similar to mesotherapy reactions). These symptoms are self-limiting and do not require intervention. There is no evidence of systemic side effects, such as alterations in blood pressure, blood glucose, or renal or hepatic function, attributable to PDRN in controlled studies. This safety profile allows PDRN to be used even in vulnerable populations, such as people with diabetes and ulcers (where many other drugs are contraindicated owing to poor circulation) or elderly patients with osteoarthritis (who may not tolerate nonsteroidal anti-inflammatory drugs or other medications). Without immunosuppressive or procoagulant effects, PDRN can be layered into standard care without added risk. For example, PDRN has been safely administered alongside antibiotics, compression therapy for ulcers, and oral analgesics without interactions.

Although no serious adverse events have been associated with PDRN, standard precautions include using an aseptic technique for injections to avoid infection and monitoring wound patients for any signs of local infection (since they are inherently at risk, although PDRN itself does not increase that risk). As a DNA-derived product, theoretical concerns about transmissible agents have been allayed by rigorous purification and sourcing from controlled environments; PDRN is not a blood product and has no risk of viral transmission. Some PDRN formulations are combined with other components (e.g., PDRN + HA gel); therefore, one should refer to those specific components for any additional precautions (for instance, HA is also very safe, but if lidocaine is included for pain relief, lidocaine precautions are applied). The safety profile of PDRN allows it to be a versatile therapy that can be confidently added to patient regimens with minimal monitoring beyond usual care.

Current evidence supports the use of PDRN in wounds and osteoarthritis; however, future large-scale trials may extend its use. Potential areas of research include rheumatoid arthritis (leveraging the anti-inflammatory effect observed in animal models) and other autoimmune conditions in which tissue damage is a concern. Chronic inflammatory diseases, such as inflammatory bowel disease and chronic periodontitis, may also benefit from the dual action of PDRN in promoting repair and modulating inflammation [42]. High-quality clinical trials under these conditions would clarify the role of PDRN and pave the way for new therapies (e.g., a trial of PDRN enemas or injections in ulcerative colitis for mucosal healing could be envisioned based on preclinical data).

Future use of PDRN will likely involve combining it with other regenerative strategies for achieving additive or synergistic effects. The first is a combination of growth factors and cell therapies. For instance, PDRN can be co-delivered with platelet-rich plasma or stem cell injections to boost the extracellular matrix (via PDRN effects) and cellular repair engines. Another promising combination is PDRN + HA, as already tested in knee osteoarthritis, which showed improved outcomes compared to HA alone [41]. A similar combination has been tested in dermal fillers (to enhance longevity and tissue integration) and ophthalmology (PDRN + artificial tears for severe dry eye healing). Additionally, PDRN with phototherapy or lasers is being explored (for example, applying PDRN after fractional laser resurfacing to enhance healing and collagen remodeling in aesthetic treatments) [43].

In the bioengineering sphere, PDRN is believed to act as a bioactive scaffold. To create scaffolds that actively stimulate regeneration, research is ongoing to incorporate PDRN into novel biomaterials such as electrospun nanofiber mats for skin wounds or 3D-printed bone grafts [44]. One challenge is controlling the release kinetics of PDRN; too fast a release might shorten its effect. Therefore, future biomaterials should aim for sustained or stimuli-responsive release. Hydrogels that respond to pH or temperature to release PDRN when needed have been studied [45]. Microneedle patches loaded with PDRN offer a minimally invasive way to deliver PDRN to chronic wounds or aging skin for rejuvenation. Moreover, the production of synthetic or recombinant PDRN (e.g., microbially derived PDRN) is an area of interest [46]. If PDRN chains could be produced via engineered bacteria or enzyme systems, it might allow for specific size ranges or modifications and alleviate the dependency on fish sources. A recent report successfully produced PDRN fragments using a microbial system and showed that they retained their efficacy in wound healing assays [45]. This could lead to more standardized products and reduced costs.

Future research will also delve deeper into the mechanisms of PDRN at the molecular level. For instance, the relative contributions of the A2AR vs. salvage pathway in different contexts (wound vs. cartilage vs. muscle) have not been fully elucidated, and understanding this could optimize the use of PDRN (e.g., pairing it with an adenosine uptake inhibitor such as dipyridamole may prolong its A2AR-mediated action [47], which could be tested in therapy). In addition, investigations into whether PDRN affects other adenosine receptors (such as A2BR in muscle differentiation) could broaden its scope [47]. If the PDRN components engage A2BR and promote myogenesis, they may also be used in muscle injury rehabilitation or sarcopenia (age-related muscle loss) [8]. The optimal dosing and route for each indication is another area for refinement. For example, could oral PDRN (if formulated to survive digestion) provide systemic benefits for conditions such as peripheral artery disease? Alternatively, is the future focused on localized delivery systems? However, these questions remain to be answered.

As PDRN use has become more common, accumulating data on long-term outcomes is essential. Do chronic wounds healed with PDRN have lower recurrence rates? Are scars more pliable? Do repeated PDRN injections delay the need for joint replacement over the years? Such long-term benefits, if demonstrated, will solidify the place of PDRN in standard treatment algorithms. Additionally, with the expansion of PDRN use geographically and into new patient populations, continued pharmacovigilance is needed to ensure that its safety profile remains favorable. Thus far, all evidence has been reassuring; nevertheless, vigilance is prudent.

Finally, future directions include achieving broader regulatory approval and incorporation into clinical guidelines. It is ongoing, and future trials could support approval by agencies such as the Food and Drug Administration or European Medicines Agency for indications such as diabetic foot ulcers or knee osteoarthritis. With formal approval, usage would increase, and more practitioners would gain experience with PDRN. Professional society guidelines (for wound care or osteoarthritis management) may begin to include PDRN as more Level I evidence emerges (e.g., if another large RCT corroborates the diabetic ulcer trial, wound care guidelines may list PDRN injections as a recommended adjunct for non-healing ulcers). In South Korea and Italy, PDRN has already been integrated into practice; the hope is that other regions will follow as data and experience grow.

In conclusion, the future of PDRN is bright, with multiple exciting avenues for expanding its therapeutic impact. This unique dual mechanism provides a platform that can be constructed using new technologies and combined approaches. As research continues, PDRN may evolve from a niche regenerative therapy to a mainstream component of healing-focused medical care used in engineering tissues for the everyday management of chronic diseases.