Trapzyme as multimodal Janus nanoplatform for apoptosis-based immunotherapy of periodontitis

Accumulation of pro-inflammatory macrophages caused by apoptosis deficiency is a major contributing factor for periodontitis progression. Inducing apoptosis of these macrophages is thus a promising approach for periodontitis management but faces multiple challenges including off-target effects, bacterial infection, redox imbalance and pro-inflammatory stimulus. Herein, we present a multimodal nanoplatform, termed Trapzyme, comprising a gelatin-bilirubin conjugate core and a macrophage membrane shell functionalized with photosensitizer cyanidin 3-O-glucoside-iron coordination and macrophage-targeting ligand phosphoethanolamine-polyethylene glycol-folate. With this design, Trapzyme is found to function as smart "iron trap" for infection control by leveraging bacterial siderophilic behavior. Upon near-infrared (NIR) irradiation, it enhances bacterial eradication via oxidative stress mechanism while inducing mild photothermal stress to trigger lysosome-mediated apoptosis in pro-inflammatory macrophages. Notably, Trapzyme is endowed with potent reactive oxygen species scavenging activity for rapid restoration of extracellular and intracellular redox balance after phototherapy. This NIR-switchable Janus-faced redox activity of Trapzyme synergically contributes to macrophage homeostasis with its neutralization of pro-inflammatory factors. Due to these multifaceted functions, NIR-tunable Trapzyme delivered by microneedles shows favorable efficacy in periodontal remodeling in mice with periodontitis, providing a precise, programmable and effective strategy for apoptosis-based immunotherapy of periodontitis.