United We Stand: Liposome Fusion Elevates the Nebulization Stability of Artificial Cell‐Derived Vesicles

Effective pulmonary drug delivery necessitates synergistic integration of functional carriers with optimized administration routes. Notably, inhalation administration of artificial cell‐derived vesicles (ACDVs) has emerged as a compelling therapeutic paradigm. However, while ACDVs leverage cell‐inherent bio‐functionality for lung cancer targeting, their lipid‐protein fragility under nebulization shear stress causes structural collapse and drug leakage. To address this challenge, a lipid fusion strategy, engineering lipid‐hybridized nanovesicles (LNVs) is developed through coextrusion of ACDVs with liposomes (LIPs), creating composite membranes with cholesterol‐enhanced ordering. LNVs are verified to exhibit the homogeneous lipid‐protein integration while preserving parental membrane proteomics. Clinically relevant nebulization (vibrating mesh/jet) assessments demonstrated LNVs’ superior stability: minimal hydrodynamic diameter variation (<10 nm vs. > 50 nm for ACDVs) and controlled polydispersity at low lipid ratios, addressing particle aggregation. Notably, LNVs retained 87% tumor‐targeting efficiency postnebulization, demonstrating comparable performance to nonnebulization ACDVs. Furthermore, they maintained >90% cell viability across lung cell lines BEAS‐2B and exhibited excellent bio‐compatibility. This stabilization strategy preserved critical bio‐functionality and reinforced biological vesicles against nebulization instability without additional sophisticated surface modifications. The simplicity and scalability of such methodology highlight transformative potential for pulmonary delivery of complex biologics.