Pathology‐Targeted Nanoparticles Guided by Peptide Remodel the Periodontal Microenvironment for Periodontitis Therapy

ABSTRACT

Periodontitis is an inflammatory and destructive condition, conventional therapies yield inadequate long‐term efficacy and possess limited regenerative potential, while the diseased microenvironment driven by inflammation and oxidative stress further hampers tissue repair. Crucially‌, because of the unique nature of the periodontal microenvironment, limitations still exist, such as a short drug retention period and low drug delivery efficiency. To overcome these limitations, we developed a new nanoplatform designed to improve local drug retention and target the core pathological mechanisms of periodontitis. Comprising cyclic Arg‐Gly‐Asp (cRGD) modified Zeolitic Imidazolate Framework‐8 (ZIF‐8) and loaded with the dual‐action agent Syringic Acid (SA), these nanoparticles create a local drug reservoir through enhanced cellular uptake, SA@ZIF‐8‐cRGD showed the time‐sequence regulation of cellular inflammation and oxidative stress levels. This nano‐platform orchestrates sequential therapeutic actions: initial rapid uptake by macrophages confers anti‐inflammatory effects, then restores the osteogenic potential of human periodontal ligament stem cells (hPDLSCs) by decreasing oxidative stress, partly through the metallothionein protein family. In the periodontitis model, SA@ZIF‐8‐cRGD significantly attenuated periodontal inflammation and promoted tissue regeneration. Collectively, our findings indicate that SA@ZIF‐8‐cRGD achieves excellent periodontitis treatment outcomes by temporally regulating multiple cells across the entire anti‐inflammatory‐regenerative pathway. This unveils a promising material‐based strategy for managing clinical periodontitis.