Harnessing Gradient Topography and Dual‐Mode Bioactive Delivery via Bone‐Adhesive Exosome Mimetics for Rotator Cuff Tendon–Bone Interface Repair

ABSTRACT

Rotator cuff repair frequently fails because the native enthesis relies on a continuous structural and compositional transition from tendon to bone. Here, we present an enthesis‐mimetic, dual‐gradient scaffold that couples a continuous random‐to‐aligned fiber orientation gradient with graded hydroxyapatite mineralization and quercetin‐loaded, alendronate‐conjugated exosome mimetics (EMQ ^A ) for spatially programmed healing. A modified electrospinning collector locally modulated the electric field to generate the orientation gradient in a single deposition process, followed by region‐dependent mineralization to create a tunable apatite interface. EMQ ^A was engineered via bioorthogonal chemistry and immobilized on the mineralized scaffold through alendronate–hydroxyapatite affinity, enabling mineral‐dependent retention and presentation. In vitro, the platform elicited region‐selective lineage responses, with enhanced osteogenic signaling on the mineral‐rich random region and chondrogenic/tenogenic‐associated profiles on the aligned region, accompanied by differential RUNX2 nuclear localization. In a preclinical rotator cuff repair model, the dual‐gradient mineralized PCL/silk/quercetin (PSQ) scaffold with EMQ ^A immobilization (PSQm@EMQ ^A ) scaffold promoted improved mineralized tissue formation by micro‐CT, more organized interface remodeling with increased osteogenic/fibrocartilaginous markers, reduced lipid deposition at the repair site, and superior mechanical performance compared with controls. This work establishes a scalable strategy to integrate structural gradients with mineral‐affinitive bioactive delivery to recreate enthesis‐like microenvironments and enhance tendon‐to‐bone healing.