Using Hybrid Nanoplatforms to Combine Traditional Anti-Inflammatory Drug Delivery with RNA-Based Therapeutics for Macrophage Reprograming

There is growing evidence on the significant role of prolonged inflammation in triggering and progressing of numerous diseases with substantial health and socioeconomic impacts, such as musculoskeletal, cardiovascular and autoimmune disorders, and cancer. Therefore, there is an urgent need to develop therapies that can overcome the main challenges of currently used approaches, such as non-target action, partial modulation of the complex inflammatory pathways, and short-term effects, to effectively manage and resolve chronic inflammatory states. This work investigates the therapeutic synergy of clinically relevant anti-inflammatory agents approaching naïve and classically activated macrophages owing to their central role in inflammation. Aiming at human therapies, a dual-loading nanoplatform reunites molecules with different physico-chemical properties in a single system, seeking to more effectively and comprehensively regulate macrophage functions for precision cell guidance and greater versatility in disease managing. To build this platform, palmitic acid <i>grafted</i> chitosan, superparamagnetic iron oxide nanoparticles, the clinically approved NSAID celecoxib (also known as Celebrex^®), and RNA technologies were combined into superparamagnetic polymeric micelles (SPMs). Our findings demonstrated that traditional anti-inflammatory drugs such as celecoxib and microRNA molecules were efficiently delivered by the SPMs, altering the inflammatory profile of naïve (M0φ) and M1-primed macrophages (M1φ) assessed by gene and protein expression. The impact of the dual-loaded SPMs in naïve Mφ is an interesting finding towards the modulation of the initial immune response, reducing the potential for chronic inflammation and promoting tissue healing. Collectively, these encouraging results demonstrate the promise of multi-nanomedicine strategies to enhance the efficacy of therapeutic interventions by offering a fresh approach to more precisely and carefully regulated nanotherapeutics delivery.