Real-World Effectiveness and Safety of Intra-Articular Polynucleotide for Knee Osteoarthritis: Large Multicenter Observational Study with Repeated Treatment

<b>Background/Objectives</b>: 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. <b>Methods</b>: 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 (<i>n</i> = 45) received a second PN cycle 6 months later. First-cycle outcomes were compared with PN-HA RCTs. <b>Results</b>: In the first-cycle (<i>n</i> = 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; <i>p</i> < 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 (<i>n</i> = 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; <i>p</i> < 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. <b>Conclusions</b>: 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.