A Citrulline-Functionalized Patch Coordinates Macrophage NRF2 Signaling and Arginine Metabolism for Tendon-to-Bone Repair.

Abstract

Structural retear remains common after rotator cuff repair. Persistent inflammation and metabolic dysfunction at the enthesis may impair healing, yet current augmentations rarely address this immunometabolic state. Exploratory single-cell profiling shows a higher proportion of M1-like cells among recovered macrophages in injured supraspinatus than in non-injured semitendinosus specimens (three donors per group). Metabolomics of polarized macrophages identifies glutathione redox imbalance and reduced arginine and proline abundance in the M1 state, supporting redox regulation and arginine metabolism as complementary targets. In ACGQD@pPLG, citrulline-functionalized, glutathione-derived carbon dots are encapsulated in an H2O2-responsive membrane coating from ultraviolet-treated tendon-derived stem cells and embedded in aligned core-shell electrospun fibers. In macrophages, the patch activates nuclear factor erythroid 2-related factor 2 (NRF2) signaling and increases argininosuccinate synthetase 1 (ASS1) expression and arginine-associated metabolite abundance. ASS1 knockdown attenuates CD206 induction, whereas NRF2 knockdown reduces HO-1 and NQO1 induction. In rats, the patch improves enthesis collagen organization and increases ultimate stress, stiffness, and load to failure to 1.6-2.5 times repair-only values at 8 weeks. Rabbit enthesis histology also improves at 10 weeks. These results support coordinated modulation of macrophage redox signaling and arginine metabolism as a local strategy for tendon-to-bone repair.

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