Multifunctional spatiotemporally programmed microneedle patches for the reconstruction of antibacterial and immunoregenerative homeostasis in periodontitis therapy.

Abstract

Periodontitis is a biofilm-induced chronic inflammatory disease characterized by progressive alveolar bone loss and eventual tooth loss. Here, we developed a core-shell microneedle (MN) system featuring a rapidly dissolvable hyaluronic acid (HA) backing layer for localized periodontal therapy. Upon insertion, the HA backing rapidly dissolves upon saliva contact, enabling detachment of the patch substrate while retaining the functional microneedle tips within gingival tissues. The MNs comprise a ZIF-8-loaded, reactive oxygen species (ROS)-responsive poly(vinyl alcohol)-4-(2,3-dihydroxypropylamino)methylphenylboronic acid (PVA-TSPBA) shell and a gelatin methacrylate (GelMA) core encapsulating a cerium-metformin (CeMet) complex. In inflamed periodontal tissues, the PVA-TSPBA shell rapidly responds to the oxidative microenvironment, enabling early Zn²⁺ availability for effective antibacterial activity, while the CeMet-loaded core provides sustained antioxidant and immunomodulatory effects. The Ce-N coordination structure in CeMet enhances cerium redox cycling, facilitating efficient ROS scavenging, AMPK activation, and NF-κB suppression, thereby driving macrophage polarization toward the anti-inflammatory M2 phenotype. This immunoregulatory cascade promotes angiogenesis and osteogenesis while inhibiting excessive osteoclast differentiation, ultimately restoring balanced bone remodeling. Importantly, this functionally coordinated therapeutic progression is biologically consistent with the pathological development and healing trajectory of periodontitis. Both in vitro and in vivo studies demonstrate effective suppression of bacterial growth and inflammation, accompanied by enhanced vascularized alveolar bone regeneration, highlighting a minimally invasive and antibiotic-free therapeutic strategy for periodontitis. STATEMENT OF SIGNIFICANCE: Inflammation-driven oxidative stress and immune dysregulation represent major barriers to effective bone regeneration in periodontitis. Here, we present a multifunctional core-shell microneedle system designed to deliver biologically coordinated, spatiotemporally programmed therapy. The microneedle shell rapidly releases ZIF-8-derived Zn²⁺ to eliminate pathogenic bacteria and inhibit biofilm formation during the early infectious phase, while the core enables sustained delivery of a cerium-metformin (CeMet) coordination complex to modulate oxidative stress and immune imbalance. By coupling Ce³⁺/Ce⁴⁺ redox activity with metformin-mediated AMPK activation, CeMet suppresses NF-κB signaling, promotes M2 macrophage polarization, and establishes a pro-regenerative immune microenvironment. This temporally orchestrated antibacterial-immunoregenerative cascade closely recapitulates the biological healing sequence of periodontitis, providing a mechanistically grounded and translationally relevant strategy for inflammatory bone repair.