Local M1 Macrophage Reprogramming with Gluconic Acid-Coated Selenium Nanoparticles.

Purpose: While reprogramming tumor-associated macrophages (TAMs) using cytokines shows promise for cancer therapy, its clinical translation is limited by poor bioavailability. Essential mineral selenium (Se), via selenoproteins, is crucial for innate immunity and adaptive immunity regulation. Methods: Addressing the need for safer, more effective methods to enhance macrophage function, we leveraged the essential mineral Se to create gluconic acid-coated Se nanoparticles (GA-SeNPs). The in vivo efficacy of GA-SeNPs was assessed via intratumoral injection in a B16-F10 melanoma BALB/c mouse model, mirroring the administration route of the first virotherapy for advanced melanoma. Results: These nanoparticles successfully induced M2-to-M1 macrophage repolarization and inhibited cancer cell growth through reactive oxygen species (ROS) generation. We confirmed through transcriptomic analysis that GA-SeNPs influence the genes of key components in the biosynthesis of selenoproteins. Additionally, GA-SeNPs influence oxidative phosphorylation, inflammatory, and ribosome pathways by promoting the shift of M2 macrophages to an M1 phenotype. Crucially, in a melanoma mouse model, GA-SeNPs treatment yielded a >4-fold tumor weight reduction and effectively repolarized TAMs to an M1 phenotype while maintaining TAMs levels. GA-SeNPs inhibit cancer growth in vivo by disrupting the immunosuppressive tumor microenvironment. They maintain total TAM counts while strongly promoting M2-to-M1 repolarization. Conclusion: Their dual localization within both TAMs and cancer cells further highlights their therapeutic potential, presenting a promising strategy to advance TAM-based cancer therapies and improve clinical outcomes.