AbstractIntroductionThe mandibular profile undergoes progressive wasting with aging, and the deepening of nasolabial folds (NLFs) has a leading role. Hyaluronic acid (HA) efficiently controls tissue hydration and permeability to small and large molecules. NLFs are an acknowledged HA target; at the same time, another class of agents, PN‐HPT® (Polynucleotides Highly Purified Technology), enjoy growing acknowledgement in aesthetic medicine. This exploratory, prospective study probed the rationale of sequentially associating PN‐HPT® as a first priming agent acting in the skin followed by HA dermal filler injections for correcting moderate to severe NLFs.MethodsFollowing strict inclusion and exclusion criteria, the authors screened Caucasian ambulatory women aged 40–65 with moderate to severe NLFs and randomly selected two NLFs for each enrolled woman. Due to the purely explorative nature of the study, the authors initially planned to enroll no >10 women. According to a split‐face design, the selected right‐side NLFs received 4 ml of PN‐HPT® intradermally in the initial priming phase (“NLF Rx group”); the selected left‐side NLFs received 4 ml of saline (placebo) (“NLF Lx group”). After 3 and 6 weeks, all patients received 2 ml of subdermal cross‐linked HA over both NLF areas (4 ml overall). The total study follow‐up was 6 months after the first injection, with objective assessments, based on the qualitative and quantitative Antera 3D® and Vectra H2® skin imaging technologies, after 6 weeks and 3 and 6 months.ResultsBecause of the favorable early outcomes, the authors let enrollment progress between January and June 2020 up to a total of 20 women and 40 NLFs. All treated women completed the six‐month follow‐up without reporting side effects, even clinically minor. The Antera 3D® device demonstrated that wrinkles and skin texture significantly improved in the NLF Rx after 6 weeks (monotherapy phase) and 3 and 6 months (PN‐HPT® priming + HA phase) compared with baseline. HA levels, measured with the quantitative Vectra H2® assessment technology in the right NLFs, were significantly higher than contralaterally at both 3 and 6 months.ConclusionsAlthough conceived only as an exploratory investigation, the study confirmed that PN‐HPT® monotherapy might be a valuable and effective option to rapidly improve the skin dermis texture and quality in individuals with moderate to severe NLFs. Acting as a priming agent in the skin, PN‐HPT® prolong the clinical efficacy of cross‐linked HA. Well‐designed trials in larger treatment groups will hopefully confirm these early promising results.