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Propolis has a long ethnopharmacological history for oral periodontal diseases treatment. Propolis flavonoids are main active components for anti-inflammation and tissue protection. However, the intractable dissolution properties of propolis flavonoids and complex oral environment pose great challenges for periodontal delivery. In addition, the therapeutic mechanism as well as the therapeutic correlation of inflammation resolution and tissue regeneration remain unclear for propolis flavonoids. In this study, we constructed an in situ thermosensitive depot systems using total flavonoids from propolis-loaded cubic liquid crystals (TFP-CLC) hydrogel for periodontal delivery. TFP-CLC inhibited inflammatory cell infiltration, reactive oxygen species and the expression of inflammatory cytokines of NF-κB and IL-1β. In addition, alveolar bone and collagen were significantly regenerated after TFP-CLC administration according to micro-CT and immunohistochemistry. Mechanism studies suggested that TFP-CLC alleviated inflammation and promoted alveolar bone repair via regulating TLR4/MyD88/NF-κB p65 and RANK/NF-κB signaling pathways, respectively. Correlation analysis further confirmed that the inflammatory resolution produced by TFP-CLC could accelerate periodontal tissue regeneration. In summary, TFP-CLC is a promising multifunctional in situ thermo-sensitive hydrogel depots for periodontitis treatment. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] • We developed an ROS-responsive and scavenging bifunctional injectable CC-B-CAPE@CY-NPs hydrogel for periodontitis treatment. • The CC-B-CAPE@CY-NPs hydrogel was capable of scavenging excessive ROS and modulating polarization of M1 macrophages via regulating NF-κB signaling. • The CC-B-CAPE@CY-NPs hydrogel promotes the repair of alveolar bone by accelerating osteogenic transformation. Periodontitis is characterized by local inflammatory response and the resultant alveolar bone resorption. The elevated reactive oxygen species (ROS) level not only aggravates local inflammation but also prohibits osteogenesis. Hence, simultaneously scavenging ROS and triggering the activity of osteoblasts may produce synergism in periodontium regeneration. Herein, we developed an injectable hydrogel system, CC-B-CAPE@CY-NPs, for periodontitis treatment, in which caffeic acid phenethyl ester (CAPE), a naturally-occurring anti-inflammatory ingredient, was caged by aryl borate for ROS-responsive release. Meanwhile, the nanoparticles incorporating Chrysin (CY), another natural product with osteogenetic property, were also coated in the hydrogel. In vitro, the hydrogel was capable of scavenging the excessive ROS and modulating the polarization of M1 macrophages, highlighting its anti-inflammatory potency. In addition, its osteogenetic effect was verified by the increased ALP activity in the hydrogel-treated periodontal ligament stem cells (PDLSCs). Our studies revealed the anti-inflammatory stemmed from its ablation of NF-κB signaling, while the activation of Wnt/β-catenin cascade accounted for its osteogenetic potency. In a rat periodontitis model, the capability of reducing ROS levels, modulating macrophage polarization, and promoting osteogenesis was transformed into the recovery of destructed alveolar bone. All above, the hydrogel possesses great potential as a promising remedy for periodontitis. [ABSTRACT FROM AUTHOR]

[Display omitted] • A folic acid-modified liposome-thermosensitive hydrogel composites (FA-GEN-Lip@Gel) was developed for in situ periodontal delivery. • FA-GEN-Lip@Gel simultaneously boost inflammation resolution and osteogenic differentiation via modulating the crosstalk between macrophages and PDLSCs. • FA-GEN-Lip@Gel suppressed inflammatory response by regulating TLR4/MyD88/NF-κB axis in macrophages. • FA-GEN-Lip@Gel enhanced alveolar bone regeneration by remodeling RANKL/OPG balance of PDLSCs. Currently, the antibiotics-loaded hydrogels have not shown an over standard of clinical effects on periodontitis treatment. Abnormal crosstalk between macrophages and periodontal ligament stem cells (PDLSCs) is a key factor for unexpected clinical efficacy. Here, we reported a therapeutic strategy for the programmed intervention of macrophages and PDLSCs based on folic acid-modified liposome hydrogel composites loaded with genistein (FA-GEN-Lip@Gel). FA-GEN-Lip@Gel exhibited excellent thermos-sensitivity and injectability, could sustained-release genistein for more than 120 h. Flow cytometry showed that FA-GEN-Lip@Gel shifted macrophages from the M1 to M2 phenotype. We further confirmed the anti-inflammatory mechanisms that FA-GEN-Lip@Gel regulate TLR4/MyD88/NF-κB axis in macrophages. In addition, FA-GEN-Lip@Gel could promote osteogenic differentiation of PDLSCs via remodeling of cytokine secretion of IL-6, IL-17, TNF-α and IL-10 in macrophages, as verified by conditioned culture system. Therefore, FA-GEN-Lip@Gel significantly reduced periodontal inflammation in vivo according to ELISA, H&E and immunofluorescence staining. Meanwhile, FA-GEN-Lip@Gel promoted alveolar bone regeneration by remodeling RANKL/OPG balance and increasing osteogenic markers of ALP, BMP2 and RUNX2. Altogether, this study develops a novel liposome-hydrogel composites that can be efficiently simultaneously boost inflammation resolution and osteogenic differentiation in periodontitis via modulating the crosstalk between macrophages and PDLSCs. [ABSTRACT FROM AUTHOR]

Periodontitis is a chronic inflammatory disease initiated by pathogenic biofilms and host immunity that damages tooth-supporting tissues, including the gingiva, periodontal ligament and alveolar bone. The physiological functions of the oral cavity, such as saliva secretion and chewing, greatly reduce the residence of therapeutic drugs in the area of a periodontal lesion. In addition, complex and diverse pathogenic mechanisms make effectively treating periodontitis difficult. Therefore, designing advanced local drug delivery systems and rational therapeutic strategies are the basis for successful periodontitis treatment. Hydrogels have attracted considerable interest in the field of periodontitis treatment due to their biocompatibility, biodegradability and convenient administration to the periodontal pocket. In recent years, the focus of hydrogel research has shifted to smart stimuli-responsive hydrogels, which can undergo flexible sol-gel transitions in situ and control drug release in response to stimulation by temperature, light, pH, ROS, glucose, or enzymes. In this review, we systematically introduce the development and rational design of emerging smart stimuli-responsive hydrogels for periodontitis treatment. We also discuss the state-of-the-art therapeutic strategies of smart hydrogels based on the pathogenesis of periodontitis. Additionally, the challenges and future research directions of smart hydrogels for periodontitis treatment are discussed from the perspective of developing efficient hydrogel delivery systems and potential clinical applications. [Display omitted] • Smart stimuli-responsive hydrogels can respond to external stimuli to periodontitis treatment. • Smart stimuli-responsive hydrogels allow triggered transitions between solution and solid in the periodontal pocket. • Smart stimuli-responsive hydrogels with switchable and controlled drug release properties can be tailored. • Review the development and rational design of emerging smart stimuli-responsive hydrogels for periodontitis treatment. • Discuss the latest therapeutic strategies of smart hydrogels based on the pathogenesis of periodontitis. [ABSTRACT FROM AUTHOR]