Multifunctional therapeutic platform based on polydeoxyribonucleotide-loaded calcium carbonate particles for...

Osteoarthritis (OA) is associated with a mildly acidic, oxidative, and inflammatory joint microenvironment that accelerates cartilage degeneration and limits the efficacy of intra-articular therapies. However, currently available intra-articular therapies fail to simultaneously address the three key pathological drivers of acidosis, oxidative stress, and inflammation that sustain this self-reinforcing OA disease loop. Here, we developed polydeoxyribonucleotide-loaded calcium carbonate (PDRN-CaCO₃) particles as a multifunctional intra-articular platform that combines pH-responsive drug delivery with microenvironment modulation. PDRN-CaCO₃ particles (~2.6 μm in diameter) were prepared via aqueous precipitation through electrostatic complexation between PDRN and Ca^2 + ions, yielding partially amorphous calcite-phase particles. Compared with CaCO₃ or PDRN alone, PDRN-CaCO₃ exhibited pH-dependent PDRN release, effective antacid activity, and enhanced radical scavenging activity. In human chondrocytes, PDRN-CaCO₃ showed excellent biocompatibility, reduced intracellular reactive oxygen species, restored cell viability under oxidative stress, and significantly downregulated OA-related catabolic and pro-inflammatory genes, including ADAMTS5, MMP-3/13, COX-2, and IL-1β. In a monosodium iodoacetate-induced rat OA model, a single intra-articular injection of PDRN-CaCO₃ improved static weight bearing, preserved joint architecture, reduced cartilage erosion, maintained Safranin-O-positive proteoglycan content, and yielded the lowest Osteoarthritis Research Society International scores among all treatment groups. Collectively, these findings indicate that PDRN-CaCO₃ reverses acidosis, attenuates oxidative and inflammatory stress, and protects cartilage, supporting its potential as a disease-modifying candidate for OA therapy.