ROS-Responsive Spatiotemporal Delivery System Targeting Tendon-bone Interface for Rotator Cuff Repair

Abstract Persistent inflammation and impaired fibrocartilage regrowth remain significant barriers to healing at the tendon-bone interface (TBI) after rotator cuff injury. Addressing this complexity requires therapeutic strategies that incorporate spatiotemporal coordination. This approach simultaneously addresses the need for temporal control over inflammation and spatially targeted fibrocartilage regeneration. We developed a ROS-sensitive polymer-based drug delivery system (named CMMKT) that coordinates magnesium ion (Mg²⁺) and kartogenin (KGN) release, allowing dynamic control of bioactive agent delivery. The system was further coated with fibrocartilage cell membranes to enhance homotypic targeting specificity toward endogenous fibrocartilage cells. In vitro analyses revealed CMMKT’s initial ROS-scavenging phase preceded sustained drug release. This sequential action promoted bone marrow mesenchymal stem cell (BMSC) migration and proliferation while attenuating apoptosis. Crucially, it preserved osteochondrogenic differentiation capacity under inflammatory challenge. In a rat model of rotator cuff tear, the immunomodulatory effects driven by CMMKT successfully reinstated fibrochondro-specific matrix deposition. This intervention notably enhanced collagen maturity and substantially improved the biomechanical strength of the repaired tissue, highlighting the system's potential to bridge the gap between immunological balance and structural restoration. Transcriptomic and metabolomic evidence confirmed CMMKT's dual-action mechanism of mitigating oxidative stress while simultaneously activating pro-anabolic fibrocartilage signaling. This spatiotemporally optimized therapeutic strategy achieves synchronized inflammation resolution and region-specific cartilage regeneration at the tendon-to-bone insertion site—effectively surmounting multifaceted histological regeneration challenge.