Engineering Nanotherapeutic Strategies for Osteoarthritis Treatment

Sammanfattning: Osteoarthritis (OA), the most prevalent joint disorder, is characterized by the degeneration of cartilage tissue leading to pain, stiffness, and impaired mobility. Primarily affecting the elderly, OA can also impact athletes, postmenopausal women, and individuals with conditions like diabetes. Despite it being a predominant contributor to physical disability, the absence of disease-modifying treatments for OA highlights the critical demand for novel therapies that preserve the well-being of individuals who are at risk of developing the disease. As conventional treatment options offer limited relief and are incapable of halting OA progression, the field of nanomedicine has emerged as a promising frontier in this pursuit. Nanoscale materials such as nanoparticles (NPs) can be designed to carry a variety of therapeutic agents directly to the affected areas of the joint enabling precise and controlled therapies. In particular, NPs can circumvent the challenges faced by traditional medicines and are able to enter the cells embedded within the dense and charged cartilage extracellular matrix. Nonetheless, the limited knowledge of their interactions with complex biological environments impedes their clinical applications. The foundational principle of the nanocarrier systems explored in this thesis is based on the use of cationic NPs. By leveraging electrostatic interactions with negatively charged components within the joint, these NPs serve as optimal tools for addressing the overlooked aspects of OA drug delivery, such as a protein-rich synovial fluid (SF) and an active catabolic environment. The findings in this work cover the SF-induced protein corona formation and its substantial effects on the NP uptake into cartilage and joint-associated cells. An enzymatically active cartilage milieu was also found to hinder the NP uptake and dictate the immunological responses, thereby influencing their therapeutic potential. By illustrating the complexity of the dynamic OA environment, the investigations of the nanomaterial-cartilage interface serve as the fundamental framework for developing optimal cartilage drug delivery strategies. Accurate disease models and extensive NP characterization in a physiologically relevant environment are necessary for paving the way toward personalized approaches in medical practice.