US/ROS-responsive ALN-modified polymer nanoparticles enhance the efficacy of infiltration anesthesia through improved bone targeting and permeation.

Complex maxillofacial bone anatomy compromises the efficacy of local anesthetics. This study develops an ultrasound (US)/reactive oxygen species (ROS) cascade-responsive polylactic-coglycolic acid (PLGA) nanoparticle system for enhanced dental infiltration anesthesia and perioperative pain management. The nanoparticles, which were surface-modified with alendronate (ALN) via an ROS-cleavable thioketal (TK) linker and coloaded with bupivacaine (BUPI) and perfluorohexane (PFH), enabled enhanced bone targeting and penetration. Under US stimulation, PFH undergoes a liquid-gas phase transition, generating ROS that cleave TK linkers, switching the system from a "bone-targeting" to a "bone-penetration" state. This cascade mechanism facilitates deep tissue penetration of local anesthetics for enhanced anesthesia while enabling a dual-phase release profile: rapid US-triggered BUPI release for intraoperative analgesia and sustained diffusion for postoperative pain management. In rat models of tooth extraction and pulp injury, the system demonstrated superior efficacy over conventional BUPI, significantly increasing drug concentrations in the mandibular bone and improving pain-related outcomes. Biocompatibility was confirmed via histology and serum biomarkers. By overcoming maxillofacial bone barriers and enabling responsive, biphasic drug release, this platform represents a promising strategy to address the limitations of current local anesthetics in dentistry, reducing local anesthesia failure rates and improving perioperative pain control.