Protease-responsive protein hydrogel enabling spatiotemporal ClO2 release for precision treatment of intracellular infections and periodontitis

Abstract

Antibiotics exhibit limited efficacy against intracellular pathogens and biofilms in periodontitis, thus often leading to drug resistance and compromised the long-term therapeutic outcomes. To address this, we developed an injectable, protease-responsive protein hydrogel (CD/BSA/GEL) for inflammation-triggered delivery of chlorine dioxide (ClO 2 , CD) and osteogenic proteins. The hydrogel was crosslinked via thermal polymerization of proteins and ClO 2 stimulation, forming a three-dimensional network responsive to proteases in inflammatory microenvironments. Upon protease activation, the hydrogel undergoes controlled degradation, enabling sustained ClO 2 release over approximately 4 days to disrupt biofilms and eradicate intracellular Porphyromonas gingivalis ( P. gingivalis ), while simultaneously releasing bone-regenerative protein components to promote osteogenesis. In vitro , the hydrogel demonstrated potent antibacterial activity against planktonic bacteria, intracellular pathogens, and mature biofilms. It also exhibited excellent biocompatibility, regenerative capacity, osteogenic potential, and differentiation-promoting effects to MC3T3-E1 cells. In a rat periodontitis model, the hydrogel achieved dual anti-inflammatory and osteogenic effects: ClO 2 reduced expression levels of IL-10 and TNF-α, while sustained protein release enhanced alveolar bone regeneration. This protease-responsive, “on-demand” release system achieves spatiotemporal precision in antibacterial efficacy and tissue regeneration through adaptive degradation kinetics. The synergistic integration of antibacterial and regenerative functions establishes the CD/BSA/GEL hydrogel as a breakthrough platform for precision-guided periodontal therapy.

Topics & Concepts