Bioinspired lipid droplets nanoplatform for periodontitis therapy: Integrated antibacterial, mitochondrial repair, and immunomodulatory functions

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. This bioinspired nanoplatform (GA@LDs-CRAMP) harnesses endogenous lipid droplets to orchestrate triple defense: pathogen-responsive antimicrobial peptide release eliminates oral pathogens, mitochondria-targeted gambogic acid scavenges ROS and restores redox balance, while macrophage polarization reprogramming resolves inflammation. • Bioengineered endogenous lipid droplets integrates triple-functional periodontal therapy. • Self-driven CRAMP anchoring via pathogen-responsive recruitment without chemical modification. • Synergistic mitochondria-immune targeted hydrophobic drug gambogic acid delivery. • Exploration and validation of macrophage reprogramming through redox-immune crosstalk. • Localized therapy reduces alveolar bone loss in preclinical periodontitis models.