Abstract

Treatment of long-segment tracheal defects (LSTDs) remains challenging, driven by the confluence of infection, oxidative stress, inflammation, and poor vascularization that compromise grafts. Here, we engineer a dual-responsive core–shell nanocapsule, co-PLGA@Cu-MSN/PP, to implement a phase-adapted paradigm for tracheal reconstruction. The inner poly(lactic -co- glycolic acid) core co-encapsulates SB431542, a transforming growth factor-β1 inhibitor, and Roxadustat, a hypoxia-inducible factor-1α stabilizer, providing sustained anti-inflammatory and pro-angiogenic cues. The outer copper-doped mesoporous silica shell, gated by a poly(ε-caprolactone)–poly(ethylene glycol) copolymer, mediates pH/esterase-responsive Cu 2+ release for antibacterial and antioxidative protection. The nanocapsules eradicate bacteria, attenuate ROS and pro-inflammatory cytokines, and bias macrophages toward an M2 phenotype, while concurrently enhancing pro-angiogenic functions in vitro. When embedded in acellular dermal matrix scaffolds, they support cartilaginous ring formation and yield a tubular engineered trachea with structural, biochemical and mechanical properties comparable to native trachea. In an orthotopic LSTD rabbit model, nanocapsule-loaded graft preserves airway patency, reduce infection, oxidative stress and fibrosis, enhance neovascularization and re-epithelialization, and improve survival versus controls. Transcriptomic analysis confirms coordinated activation of antibacterial, antioxidative and angiogenic pathways and suppression of MyD88-dependent toll-like receptor signaling. Collectively, this dual-responsive core–shell nanocapsule orchestrates a spatiotemporally programmed “clearance–then–repair” microenvironment for functional airway reconstruction.