Dual‐Responsive Core‐Shell Nanocapsules Orchestrate a "Clearance–Then–Repair" Microenvironment for Tracheal Reconstruction

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.