Immuno‐Metabolic Reprogramming by EPO Delivery System Accelerates Achilles Tendon Regeneration via Macrophage Polarization and Mitochondrial Rescue

Achilles tendon repair remains a significant clinical challenge. Erythropoietin (EPO), a hematopoietic glycoprotein hormone primarily known for stimulating erythrocyte production, has recently been recognized for its immunomodulatory and regenerative properties. Notably, a recent Science study (Chiu et al., 2025) demonstrated that EPO drives macrophage polarization toward an immunoregulatory phenotype in the tumor microenvironment, underscoring its profound role in immune remodeling. However, its broader biological effects and mechanisms in tendon regeneration remain largely unexplored. In this study, we established an Achilles tendon injury model in Sprague-Dawley rats and locally administered either free EPO or pH-responsive EPO-loaded nanoparticles (EPO@NPs). Our findings show that both EPO and EPO@NPs significantly promote macrophage polarization from M0 to M2 phenotypes, restore mitochondrial integrity, and inhibit activation of the cGAS-STING signaling pathway. These effects collectively reduce local inflammation and accelerate endogenous tendon regeneration. This study not only uncovers a novel immunometabolic mechanism underlying EPO-mediated tendon repair but also builds upon recent insights into EPO's immune functions, highlighting EPO@NPs as a promising therapeutic strategy for enhancing tendon healing.