Collagenase-Responsive Hydrogel Loaded with GSK2606414 Nanoparticles for Periodontitis Treatment through Inhibiting Inflammation-Induced Expression of PERK of Periodontal Ligament Stem Cells

GSK2606414 is a new, effective, highly selective PERK inhibitor with adenosine-triphosphate-competitive characteristics. It can inhibit endoplasmic reticulum stress and has the possibility of treating periodontitis. However, owing to its strong hydrophobicity and side effects, highly efficient pharmaceutical formulations are urgently needed to improve the bioavailability and therapeutic efficacy of GSK2606414 in the treatment of periodontitis. Herein, a novel local GSK2606414 delivery system was developed by synthesizing GSK2606414 nanoparticles (NanoGSK) and further loading NanoGSK into a collagenase-responsive hydrogel. The drug release results showed that the drug-loaded hydrogels had outstanding enzymatic responsive drug release profiles under the local microenvironment of periodontitis. Furthermore, in vitro studies showed that the drug-loaded hydrogel exhibited good cellular uptake and did not affect the growth and proliferation of normal cells, while the drug-loaded hydrogel significantly improved the osteogenic differentiation of inflammatory cells. In the evaluations of periodontal tissue repair, the drug-loaded hydrogels showed a great effect on inflammation inhibition, as well as alveolar bone regeneration. Therefore, this work introduces a promising strategy for the clinical treatment of periodontitis.