Push-and-Pull Nanotherapeutics for Osteoarthritis with Drug Delivery and Dual Scavenging of Reactive Oxygen Species and Cell-Free DNA
Rajendra K. Singh, Nandin Mandakhbayar, Amal George Kurian, Shreyas Kumar Jain, Suparna Bhattacharya, Archita Gupta, Jung‐Hwan Lee, Hae‐Won Kim
Abstract
Osteoarthritis involves complex inflammatory responses, leading to cell death and joint dysfunction. Key contributors are pro-inflammatory molecules, such as excess reactive oxygen species (ROS) and cell-free DNA (cfDNA), which require effective scavenging. Concurrently, delivering anti-inflammatory agents can stimulate immune cells to restore tissue repair by resolving inflammation. Thus, a "push-and-pull" approach-combining delivery and scavenging-is optimal for osteoarthritis treatment. Here, we propose a multitherapeutic strategy using polycationic-functionalized mesoporous ceria nanoparticle (mCNP-G) to target osteoarthritic joint cartilage. The mCNP core, with its multiple catalytic capabilities and mesoporous structure, was effective in scavenging ROS and loading/releasing the anti-inflammatory drug dexamethasone. Additionally, polycationic functionalization enhanced the scavenging of cfDNA released from damaged or dying cells. These combined functions of mCNP-G substantially down-regulated pro-inflammatory signaling, thereby rescuing cells and interrupting the inflammatory feedback loop. Moreover, mCNP-G demonstrated high affinity for cartilage tissue, facilitating targeted retention to osteoarthritis region. When locally administered to rat osteoarthritic temporomandibular joint, mCNP-G with dexamethasone significantly reduced cfDNA and oxidative stress, inhibited inflammation, and salvaged cells, ultimately alleviating osteoarthritic symptoms and osteochondral damage. This nanomedicine offers a promising therapeutic strategy for osteoarthritis by integrating the push-and-pull functions of drug delivery and ROS/cfDNA dual-scavenging within a single system.