Stiffness-tuned and ROS-sensitive hydrogel incorporating complement C5a receptor antagonist modulates antibacterial activity of macrophages for periodontitis treatment

Periodontitis is admittedly a microbe-driven intractable infectious disease, in which Porphyromonas gingivalis (Pg) plays a keystone role. Pg can selectively impair the antimicrobial responses of periodontal resident macrophages including their phagocytic and bactericidal activity without interfering their proinflammatory activity, which leads to microflora disturbance, destructive periodontal inflammation and alveolar bone loss eventually. Here, an injectable ROS-sensitive hydrogel is developed for releasing active bone marrow-derived macrophages (named ex-situ macrophages hereafter) and a complement C5a receptor antagonist (C5A) to the gingival crevice. Through appropriately tuning the hydrogel stiffness, the phagocytic activity of these macrophages is greatly enhanced, reaching an optimal performance at the elastic modulus of 106 kPa. Meanwhile, C5A avoids undesired C5a receptor activation by Pg to ensure the bacterial killing activity of both the ex-situ and in-situ macrophages. Besides, the ROS-sensitive hydrogels show another distinct feature of decreasing the ROS level in periodontal niche, which contributes to the alleviated periodontal inflammation and attenuated bone loss as well. This study highlights the potential of utilizing hydrogels with tailored biomechanical properties to remodel the functions of therapeutic cells, which is expected to find wide applications even beyond periodontitis treatment.