Cationic Nanoparticle Interactions with Catabolic Cartilage Modify Macrophage Cytokine Production

Cationic nanoparticles (NPs) have emerged as promising candidates for intra-articular drug delivery, showcasing their potential as efficient carriers. However, despite their evident utility, many studies neglect to investigate their interactions with the extracellular matrix (ECM). This oversight represents a significant gap in our understanding, particularly in the context of osteoarthritis (OA) treatment, where viable therapeutic options are limited. The clinical translation of functionalize drug carriers for OA has been hindered, in part, by our incomplete comprehension of how these materials interact with and respond to the pathological environment. This study aims to address this gap by examining how cationic NPs interact with ECM components in an ex vivo OA cartilage explant model. By comparing the behavior of smaller (<10nm) and larger (~270 nm) cationic NPs and subjecting them to explants preconditioned with OA-specific catabolic enzymes, we observed multifaceted effects on ECM integrity and biomolecule conformation. All NP-biomolecule complexes induced differential cytokine production from stimulated macrophages. Smaller polyamidoamine (PAMAM) nanocarriers reduced glycosaminoglycan (GAG) release from explants but increased proinflammatory cytokine stimulation under pathological conditions, while larger poly lactic(co-glycolic)acid(PLGA)/polyethylenimine(PEI)-based nanocarriers maintained GAG release but induced a significantly lower proinflammatory cytokine response. Collagenase-induced OA-mimicking preconditioning produced distinct profiles across the NP panel in GAG interactions and cytokine production. The findings from these studies underscore the significance of tailored nanocarrier approaches to achieve optimal therapeutic efficacy for OA and other complex diseases.