Orchestrating the immuno-chondrogenic microenvironment via a bio-inorganic hybrid microsphere system for tendon-to-bone healing

The structural failure of rotator cuff repair is largely attributed to fibrovascular scar formation driven by a persistent inflammatory microenvironment and insufficient fibrocartilage regeneration at the tendon-to-bone interface. To address this, a microfluidic-generated GelMA microsphere system co-encapsulating Zeolitic Imidazolate Framework-8 (ZIF-8) nanoparticles and bone marrow mesenchymal stem cell (BMSC)-derived small extracellular vesicles (sEVs) is developed. This composite system (ZIF-8/sEVs@MS) enables the sustained release of Zn²⁺ and sEVs, which synergistically reprogram macrophages (Mφ) from a pro-inflammatory M1 phenotype to a reparative M2 state and restore the CXCL12/CXCR4 axis for endogenous stem cell recruitment. Transcriptomic analysis elucidates that the system reactivates the PI3K/AKT signaling pathway, thereby reversing inflammation-mediated inhibition and driving chondrogenic differentiation. In a rat rotator cuff repair model, the functionalized microspheres significantly enhance fibrocartilaginous enthesis regeneration, biomechanical structural integrity, and limb function. This study establishes a dual-functional "immuno-chondrogenic" strategy that coordinates immune microenvironment modulation with tissue-specific differentiation to facilitate functional tendon-to-bone healing.