Core-shell engineered Col/Cs@ECM microspheres for macrophage-targeted intracellular drug release in RA therapy.

The imbalance of macrophage polarization between M1 and M2 phenotypes in rheumatoid arthritis (RA) results in a persistent inflammatory cascade. Activating M2 anti-inflammatory polarization, which remove excess extracellular matrix (ECM) via phagocytosis, represents a potential therapeutic target for RA. This study introduces Col/Cs@ECM microspheres, a novel drug delivery system designed for macrophage recognition via a tailored ECM surface, enhancing phagocytic efficiency and accumulation. Moreover, the Col/Cs@ECM microspheres are composed of biocompatible and fully degradable materials, ensuring their safety profile within the physiological environment. Following cell phagocytosis, the collagen/chitosan (Col/Cs) core release the drug (Dexamethasone, Dex) intracellularly to inhibit M1 polarization by inhibiting the NF-κB signaling pathway and to facilitate M2 polarization. This macrophage targeted and intracellular release approach offers a significant advantage over traditional medications by reducing systemic side effects and improving the therapeutic index. The strategy prompts macrophages to express anti-inflammatory cytokines like IL-10 while suppressing pro-inflammatory cytokines such as TNF-α, thereby remodeling the immune microenvironment. Additionally, the specially engineered ECM shell of the microspheres extends the anti-inflammatory response by prolonging macrophage lifespan, a feature that is not present in conventional treatments. This results in improved treatment outcomes in an in vivo RA animal model. This research presents a possible intracellular anti-inflammatory treatment approach for rheumatoid arthritis injection therapy with the potential to outperform existing treatments in terms of efficacy and safety.