Design of tunable hyaluronic acid and O′-carboxymethyl chitosan formulations for the minimally invasive delivery of multifunctional therapies targeting rheumatoid arthritis

The development of injectable, dual-component formulations based on natural-based polysaccharides is a promising strategy for the localized treatment of rheumatoid arthritis (RA). In the present study, biomimetic formulations consisting of aldehyde-functionalized hyaluronic acid (AHA) and O-carboxymethyl chitosan (OCC) were developed, presenting rapid in situ gelation rates and finely tunable physicochemical properties. These two properties allowed for the controlled delivery of anti-inflammatory, antioxidant, and pro-regenerative agents (i.e., strontium-methotrexate (SrMTX) and europium-tannic acid nanocomplexes (EuTA NCs), making them suitable for application in in vivo RA-models. Biological analyses demonstrated the system's cytocompatibility and its ability to modulate the activity of human articular chondrocytes at the secretome level and scavenge nitric oxide (NO). Moreover, the loaded cargoes not only extended the anti-inflammatory properties of the formulation but also the radiolabeling of EuTA NCs with ⁶⁸Ga allowed the visualization of the gel by positron emission tomography (PET). Overall, this work presents the design and in vitro evaluation of an easily modulable polymeric system that allows the in situ release of a multifunctional therapy with promising perspectives for RA treatment.