Ultrathin ZIF‐8 Coating‐Reinforced Enzyme Nanoformulation Avoids Lysosomal Degradation for Senile Osteoporosis Therapy

Abstract Antioxidant enzymes are considered to be the most direct and safe candidates to effectively resist oxidative stress and treat senile osteoporosis. However, due to their size, existing enzyme delivery carriers are inevitably endocytosed by cells and subsequently enter endosomes/lysosomes with low pH and rich in acid hydrolase, resulting in the limited therapeutic effects. In this work, an ultrasmall superoxide dismutase (SOD) nanoformulation reinforced with ultrathin ZIF‐8 coating (utZIF‐SOD) via in situ coordination‐mediated self‐assembly strategy is constructed. Notably, utZIF‐SOD achieves direct, efficient cellular uptake mediated by small size effect, thereby avoiding lysosomal degradation. In particular, ultrathin ZIF‐8 coating strengthened the stability of enzyme. Even in aged cells with high oxidative stress levels, utZIF‐SOD maintained excellent stability, and its efficiency in scavenging excess intracellular reactive oxygen species (ROS) is ≈1.5 times that of native SOD, better promoting the osteogenic differentiation of aged bone marrow mesenchymal stem cells. In a senile osteoporosis mouse model, the bone mineral density increment after treatment with utZIF‐SOD is ≈2 times that of native SOD, achieving the reversal of senile osteoporosis. This work demonstrates the great promise in the synthesis of ultrasmall nanoformulations with ultrathin metal‐organic framework coating and opens new avenues for efficient enzyme delivery.