Engineered biomimetic lipid droplet nanoplatforms (GA@LDs-CRAMP) for periodontitis therapy using macrophage-derived lipid droplets with surface-anchored cathelicidin (CRAMP) and encapsulated gambogic acid. The system suppressed pathogen proliferation, restored mitochondria via ROS scavenging, reprogrammed macrophage polarization from M1 to M2, and attenuated alveolar bone resorption in preclinical models.
Abstract
Periodontitis, a multifactorial inflammatory disease driven by microbial dysbiosis, dysregulated immunity, and oxidative stress, demands therapeutic strategies that concurrently address interconnected pathological pathways. Here, a biomimetic lipid droplet-based nanoplatform (GA@LDs-CRAMP) is engineered to achieve spatiotemporal coordination of antibacterial, antioxidant, and immunomodulatory functions for the treatment of periodontitis. Constructed using RAW264.7 macrophage-derived lipid droplets (LDs), the GA@LDs-CRAMP system anchors cathelicidin-related antimicrobial peptide (CRAMP) onto LDs surfaces via lipopolysaccharide (LPS)-stimulated recruitment, while encapsulating gambogic acid (GA) within its hydrophobic core for mitochondria-targeted delivery. The nanoplatform demonstrates comprehensive therapeutic efficacy against periodontitis by suppressing periodontopathogen proliferation, restoring oxidative stress-damaged mitochondria through reactive oxygen species (ROS) scavenging, inhibiting inflammatory cascades via nuclear factor erythroid 2-related factor 2 (Nrf2)/nuclear factor-kappa B (NF-κB)-mediated antioxidant signaling activation, and reprogramming macrophage polarization from pro-inflammatory M1 to tissue-reparative M2 phenotypes. In preclinical periodontitis models, localized delivery of GA@LDs-CRAMP effectively mitigates inflammatory cytokine storms and attenuates alveolar bone resorption. Collectively, this study demonstrates the potential of leveraging lipid droplets organelles to engineer precision-targeted, multifunctional drug delivery systems for periodontitis therapy.