ABSTRACT The latest census indicates that 50+ million adults in the US bear some form of arthritis and by 2030, an estimated 67 million Americans ages > 18 years are projected to have the diagnosis of arthritis. Osteoarthritis (OA) represents the most common form of arthritis and is a major cause of morbidity in the aging population but for which there are limited medical treatments and no disease modifying drugs. Although effective disease- modifying OA drugs (DMOADs) are critically needed, none has successfully emerged in the clinic. Post- traumatic OA (PTOA) is a form of OA that develops after a joint injury and in which the nature and time of trauma is generally known. Approximately 12% of the overall OA burden can be traced to joint trauma. True prevalence for PTOA may be higher, given the long delay between injury and PTOA (10-15 years). PTOA affects 5.6 million individuals in the US. The projected lifetime risk of developing PTOA of the knee in individuals who sustain anterior cruciate ligament (ACL) rupture or meniscal damage is 50-70%. PTOA accounts for 20% of all joint replacements. Veteran Health Relevance: Among the population of service members, all causes of PTOA result in some degree of permanent disability in 28% of soldiers compared to 12% of civilians who sustain joint trauma. In addition, the frequency of arthritis among combat veterans from ongoing US military operations is estimated at 11.8%. The diagnosis of arthritis resulting from combat-related injury is accelerated and often accompanied by poor outcomes, requiring joint replacement at a younger age in the veteran population compared to the general population. Thus, any intervention that shifts the curve and decreases the risk of PTOA development will benefit the patients in the general population as well as military service members and veterans. Studies have documented a robust inflammatory response in the immediate aftermath of joint injury (i.e. during the first week up to 2-3 months) that persists for months to years, albeit at a lower level. This inflammatory response likely contributes to chondrocyte death, impaired cartilage repair and the subsequent cartilage degeneration that characterizes PTOA. We posit that modulation of this early inflammation limits acute cartilage damage while delivery of an anabolic factor that promotes cartilage repair/homeostasis will further delay or prevent eventual PTOA development. We employed a peptide-based self-assembling nanocomplex, delivering a wide range of nucleic acids [small interfering (si)RNA and messenger (m)RNA] and allowing for the simultaneous targeting of multiple pathways using the same cell-penetrating peptide, with no need for backbone or end-piece alterations. We show that intra-articular (IA) delivery of our peptide-based nanoparticle to knock down expression of NFKB mitigates early established PTOA in the Destabilization of the Medial Meniscus (DMM) model of surgery-induced PTOA. We also demonstrate that simul...