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The integration of nanomaterials into 3D network materials holds great potential in the improvement of key mechanical properties, particularly important for osteochondral replacement scaffolds and even to function as carriers for disease\u2010modifying drugs or other regulatory signals. In this study, a simple yet effective cell\u2010free nanoenabled Col\u2010PLA scaffold specially designed to enhance cartilage regeneration and modulate inflammatory response is proposed, by incorporating poly(lactic\u2010co\u2010glycolic acid) (PLGA) ibuprofen nanoparticles (NPs) into a collagen\/polylactide (Col\u2010PLA) matrix. The developed nanoenabled scaffold successfully decreases IL\u20101\u03b2 release and leads to primary human chondrocytes survival, ultimately restoring extracellular matrix (ECM) production under inflammatory conditions. The nanoenabled Col\u2010PLA scaffolds secretome effectively decreases macrophage invasion in vitro, as well as neutrophil infiltration and inflammatory mediators\u2019, namely the complement component C5\/C5a, C\u2010reactive protein, IL\u20101\u03b2, MMP9, CCL20, and CXCL1\/KC production in vivo in a rodent air\u2010pouch model. 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