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

Persistent inflammation and impaired fibrocartilage regeneration hinder the healing of the tendon-bone interface (TBI) following rotator cuff injury. To address this challenge, we propose a spatiotemporally coordinated therapeutic strategy that combines the temporal control of inflammation with targeted fibrocartilage regeneration. A multifunctional nanomedicine delivery system, designated as CMMKT, was developed using reactive oxygen species (ROS)-responsive polymers to control the release of magnesium ions (Mg²⁺) and kartogenin (KGN). The delivery system was coated with fibrochondrocyte cell membranes to improve spatial specificity in targeting fibrocartilage cells. CMMKT enhanced the migration and proliferation of bone marrow mesenchymal stem cells (BMSCs) <i>in vitro</i> under inflammatory conditions, inhibited apoptosis, restored osteogenic and chondrogenic differentiation capacities, and increased the proportion of M2 macrophages by scavenging ROS and facilitating sustained drug release. In a rat rotator cuff tear model, CMMKT-driven immunomodulation restored fibrochondrocyte-specific matrix deposition, leading to an increased collagen maturity and biomechanical strength. Transcriptomic and metabolomic analyses indicated the suppression of oxidative stress responses and the activation of anabolic pathways in fibrocartilage. Overall, this spatiotemporal coordination therapeutic concept, CMMKT, is a promising approach for TBI repair that integrates inflammatory microenvironment reprogramming with the targeted enhancement of fibrocartilage regeneration.