Engineering of an mRNA- based theranostic platform for joint repair

Osteoarthritis (OA) is one of the most prevalent chronic diseases in developed countries and, in the United States alone, around 27 million adults over 25 years old have been diagnosed with OA of any joint. In approximately 12% of OA cases, symptoms arise after joint injury: when OA develops after a trauma, it is defined as post traumatic osteoarthritis (PTOA). Direct costs for PTOA treatments reached peaks of $3 billions annually and, as the injury rates increase, so will the financial burden on the healthcare system. Moreover, current therapies remain ineffective, mostly providing some palliative care or pain management, and any treatment capable to slow down or reverse the progression of the disease is yet to be found, leaving patients with surgical interventions (arthroplasties, osteotomies, joint fusions, and joint replacements) as their only option. It is clear that finding successful treatments for this pathology would have a great impact on both the healthcare system and the welfare of the population. Recent studies have shown interest in investigating the use of nanomedicine to develop Drug Delivery Systems (DDSs) for OA. The lack of targeted of therapies for PTOA patients has warranted the development of novel strategies for targeting the injury sites while delivering therapeutics aimed at addressing the underlying drivers of disease. Translation of nanoparticles (NPs) to the clinic has been hampered by the limited ability of synthetic nanoparticles to overcome the biological barriers posed by the complex in vivo milieu. In order to overcome these limitations, nanoparticles designed to mimic native cells through the integration of cell membrane components have been developed. In particular, leukocyte-mimicking lipid nanoparticles have demonstrated the ability to target sites of inflammation, evade immune clearance and deliver therapeutic molecules. Leveraging on the advantages of this technology, this study aimed to demonstrate the utility of these biomimetic nanoparticles for the targeting and treatment of PTOA injuries. In fact, engineering of NPs was explored from two perspectives: (i) a biological approach aimed at improving the targeting abilities of the nanoparticles towards PTOA injury sites, and (ii) a cargo-based approach for the development of NP formulation capable of delivering therapeutic RNA molecules. By combining these two approaches for the engineering of leukocyte mimicking nanoparticles, a novel theranostic system for targeting and treating PTOA in the acute phase after trauma was developed, while gaining important insights for the future development of these cell mimicking nanoparticle platforms.

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