A stalactite-inspired NIR/pH-responsive visualizable nano-platform for microenvironment-activated therapy of peri-implantitis-induced bone defects

Peri-implantitis is an inflammatory disease characterized by progressive peri-implant bone resorption. It poses a substantial challenge to the long-term survival of dental implants and imposes a considerable therapeutic burden. As the early stage of peri-implantitis is typically asymptomatic and difficult to detect, the optimal intervention window is often missed. Current reconstructive approaches primarily rely on invasive debridement or bone grafting, underscoring the need for a multifunctional therapeutic strategy that combines diagnostic capabilities, anti-inflammatory, and osteogenic properties. Inspired by the biomineralization process of stalactites, we developed a biomimetic composite CIMA (ACC@ICG/AZM@ALD) by encapsulating indocyanine green (ICG) and azithromycin (AZM) into amorphous calcium carbonate (ACC) and coating its surface with the bone-targeting ligand alendronate (ALD), thereby imparting the nanoplatform with antibacterial, anti-inflammatory, and osteoinductive properties. The introduction of AZM reshaped the peri-implant immune microenvironment and synergized with ICG, an FDA-approved NIR dye, to enhance antibacterial efficacy. In vitro assays demonstrated that CIMA could responsively trigger near-infrared (NIR) fluorescence upon exposure to the bone defect microenvironment, providing real-time visual warning. Furthermore, CIMA effectively scavenged reactive oxygen species (ROS), alleviated oxidative stress, and exerted potent anti-inflammatory and antibacterial effects against Staphylococcus aureus ( S. aureus ) and Streptococcus mutans ( S. mutans ). Concurrently, it promoted the osteogenic differentiation of bone marrow–derived cells while suppressing osteoclastogenesis. In vivo , using a rat peri-implantitis model, CIMA facilitated bone regeneration within the inflamed peri-implant region. Collectively, this artificially engineered, stalactite-inspired CIMA system promoted bone regeneration and provided combined anti-inflammatory and antibacterial functions, offering a promising strategy for treating peri-implantitis. Graph 1. Schematic illustration of the preparation of NIR/pH-responsive visualizable nano-platform for microenvironment-activated therapy of peri-implantitis-induced bone defects, and its therapeutic application for peri-implantitis. A) Establishment of a Sprague–Dawley (SD) rat peri-implantitis bone defect model. In response to a defective microenvironment, CIMA releases therapeutic payloads and enables lesion-confined fluorescence reporting for early visual warning. B) Upon near-infrared (NIR) irradiation, CIMA provides synergistic antibacterial/anti-biofilm decontamination at the peri-implant site. C) Concurrent anti-inflammatory immunomodulation alleviates the local inflammatory burden and supports osteogenic regeneration. D) Schematic illustration of peri-implant bone defect repair after treatment.To validate therapeutic efficacy, we established an intraoral Sprague–Dawley rat peri-implantitis bone defect model following an “immediate extraction–immediate implantation” protocol (Graph 1A). Under neutral conditions, CIMA remains stable and co-encapsulates ICG and AZM; upon peri-implantitis–associated acidification within the defect niche, the ACC component disintegrates to release both agents while switching on ICG fluorescence for lesion-confined, real-time visual early warning (Graph 1A). Subsequent 808 nm NIR irradiation activates ICG to generate singlet oxygen ( 1 O 2 ) and mild hyperthermia, thereby achieving synergistic photodynamic/photothermal antibacterial and anti-biofilm decontamination at the peri-implant site (Graph 1B). In parallel, released AZM modulates macrophage polarization to alleviate the inflammatory burden and support osteogenic regeneration (Graph 1C), ultimately facilitating peri-implant defect repair (Graph 1D) through enabling an image-guided, sequential “monitoring–therapy–regeneration” strategy. • CIMA provides microenvironment-responsive antibacterial activity with early NIR fluorescence warning. • CIMA suppresses oxidative stress and key inflammatory pathways to stabilize the peri-implant immune microenvironment. • CIMA promotes osteogenesis within inflamed peri-implant bone defects.