Smart Implant Coating with Pathological-Microenvironment-Driven Drug and Nanozyme Delivery for Osteoporotic Bone Healing.

Stimuli-responsive drug delivery from orthopedic implants holds particular promise for enhancing osseointegration in osteoporotic bone. However, challenges such as the lack of feedback-regulated functionality and microenvironmental modulation persist. Here, we developed an osteoporotic microenvironment-responsive implant coating that integrates feedback-regulated release of the anti-osteoporotic drug strontium ranelate (SR) with oxidative stress neutralization. A reactive oxygen species (ROS)-responsive and -regulating nanocoating was fabricated on SR-loaded titania nanotube arrays (TNTAs-SR) via host-guest complexation between β-cyclodextrin-conjugated ceria nanoparticles (CeNPs-β-CD) and ferrocene-modified polydopamine (PDA-Fc). The CeNPs-β-CD served dual roles as antioxidant nanozymes and ROS-responsive nanolids through reversible β-CD/Fc interactions. The resulting PDA-CeNP nanocoating exhibited exceptional antioxidative capacity against multiple ROS through the combined action of PDA-Fc and CeNPs-β-CD. Owing to its reversible redox sensitivity, TNTAs-SR/PDA-CeNPs enabled rapid SR release under high H2O2 levels and delayed release upon H2O2 depletion, achieving "sense-feedback" drug delivery. In vitro, TNTAs-SR/PDA-CeNPs had greater protective effects on osteoblastic functions against H2O2-induced oxidative stress and attenuated osteoclast differentiation. In an osteoporotic rat model, TNTAs-SR/PDA-CeNPs eliminated ROS and lipid peroxidation in bone tissue, inhibited fibrosis, and maximally enhanced osseointegration. Overall, this smart implant coating, capable of rescuing the pathological ROS microenvironment while delivering therapeutic agents on demand, holds substantial promise for osteoporotic bone healing.