Core–Shell Codelivery Nanocarrier Synergistically Regulates Cartilaginous Immune Microenvironment for Total Meniscus Replacement

Cartilage tissue engineering has made significant strides in clinical regenerative treatment. The success of cartilage regeneration critically depends on a favorable regenerative microenvironment by means of ideal bioactive scaffolds. However, total meniscus replacement frequently entails a harsh microenvironment of accompanying chronic inflammation and oxidative stress conditions after a massive injury, which extremely hinders tissue regenerative repair. Herein, a "core-shell" codelivery nanocarrier is developed to synergistically regulate the cartilaginous immune microenvironment (CIME) for total meniscus replacement. In this study, mesoporous silica nanoparticles are used to encapsulate an antioxidant and anti-inflammatory drug, Emodin, in the core and meanwhile modify a growth differentiation factor (GDF) by reversible disulfide bonds on the shell, together constructing a codelivery nanocarrier system (<b>Em@MSN-GDF</b>). The synergistic dual-drug release effectively reverses inflammation and oxidative microenvironment and is followed by successful promotion of fibrocartilage regeneration <i>in vivo</i>. Subsequently, <b>Em@MSN-GDF</b>-loaded cartilage-specific matrix hydrogels are combined with a meniscus-shaped polycaprolactone framework to construct a mechanically reinforced living meniscus substitute. As a result, rabbit experiments demonstrate that the codelivery nanocarrier system synergistically regulates the cartilaginous immune microenvironment, thereby achieving successful total meniscus replacement and fibrocartilage regeneration. The current study, therefore, offers a regenerative nanotreatment strategy to reverse the harsh microenvironment for total meniscus replacement.