Introduction

Periodontitis is a chronic inflammatory disease with clinical manifestations such as bleeding gums, recurrent swelling and pain, and resorption of alveolar bone. If inadequately treated, it can lead to loosening and loss of teeth, chewing function, and even effects on the digestive system [1]. In the world, periodontitis affects 11% of the global population, with prevalence rates ranging from 8 to 46% in develo** countries and 3–18% in developed countries [2]. Periodontitis is more common in the aged due to chronic and cumulative injury. Two thirds of people over 65 years old in the United States have chronic periodontitis [3]. In recent decades, the incidence and prevalence of severe periodontitis in Asian countries, such as India, China and Japan, has been on the rise, and age may be a critical factor for the increasing trend [69, 70]. Chlorin e6 (Ce6) is widely used in PDT therapy because of its strong tissue penetration, great biocompatibility and high yield of singlet oxygen [71, 72]. Sun et al. prepared a core–shell structure nanodrug delivery system (Fe3O4-silane@Ce6/C6) including Fe3O4 nanoparticles, Ce6 and coumarin 6, for PDT antimicrobial therapy [73]. Transmission electron microscopy (TEM) images of Fe3O4 nanoparticles show a diameter of approximately 8 nm and Fe3O4-silane@Ce6/C6 a diameter of about 100 nm. Fe3O4-silane@Ce6/C6 produced O2− under light irradiation and had a killing effect on Streptococcus sanguis, Pg and Fn Under light irradiation, Fe3O4-silane@Ce6/C6 reduced Fn and Pg biofilm colony formation units by approximately 4 log and 5 log, respectively. Notably, Fe3O4-silane@Ce6/C6 can be magnetically induced to concentrate at plaque biofilm sites to further enhance the antibacterial effect. These results indicate that PDT combined with magnetic targeted nanoparticles has potential for antimicrobial therapy for periodontitis.

Although PDT has made important progress in the treatment of periodontal disease, there are some serious problems that still need to be solved before clinical application. The most important limitation of conventional PDT is the weak tissue penetration of ultraviolet or visible light. Therefore, it is highly desirable to design and prepare a PDT system that relies on with the infrared irradiation light, which can perform deep-tissue penetration. Based on this, a strategy was proposed to combine the photosensitizer Ce6 with upconversion nanoparticles (UCNPs) NaYF4:Yb, Er [74]. The combination of Ce6 UCNPs was realized via an amphiphilic silane modification technique (NaYF4@Ce6@silane NPs), which involved the hydrophobic-hydrophobic interaction between the hydrophobic side chain of the silane and hydrophobic groups on the surface of UCNPs [75]. In addition, because the PDT function of the Ce6 molecule should be triggered by excitation by red light, Mn do** is involved in this work, which greatly improves the probability of the red emission transition (NaYF4-Mn@Ce6@silane) (Fig. 4A). The TEM image showed that the size distribution of NaYF4@Ce6@silane NPs was approximately 30 nm, and a thin layer of silane (approximately 2–3 nm) was observed on the surface of the nanoparticles after silane coating. The result showed that 30% Mn was selected to dope into UCNPs to realize the enhancement of red-light emission, and the enhanced upconversion red emission can further improve the PDT effect. The colony forming units of Pg, Fn and P. intermedia after NaYF4-Mn@Ce6@silane NPs with 980 nm irradiation decreased by more than 2 log, and the biofilm matrix was easily disrupted with deeper penetration of infrared light. This highly efficacy against periodontitis-related biofilms should be attributed to the high hydrophilic surface after silane modification, as well as to the upconversion luminescence triggered PDT. This upconversion PDT design can overcome the problems of conventional PDT and provide effective nano strategies for the treatment of periodontitis.

Fig. 4
figure 4

Schematic illustration of periodontitis treatment by photothermal/photodynamic therapy. A The schematic diagram of NaYF4-Mn@Ce6@silane. Reprinted with permission from Ref. [74] Copyright Multidisciplinary Digital Publishing Institute. B Preparation and against periodontitis of TAT-Ce6/TDZ NPs. Reprinted with permission from Ref. [76] Copyright American Chemical Society. C Preparation of sPDMA@ICG NPs and treatment of synergistic PTT and PDT on periodontitis. D TEM images of bacteria after processions of PBS (the control), sPDMA@ICG NPs with and without laser irradiation. E Photos of plaque biofilms after various processions. F Comparison for the mean fluorescence intensities of produced DCF in periodontium. Infrared thermal images of periodontium during laser irradiation after administration of PBS (the control) and sPDMA@ICG NPs. **indicates p < 0.01 compared to the control (+); ##indicates p < 0.01 for comparison between two groups. Reprinted with permission from Ref. [79] Copyright Springer Nature

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However, PDT does not always achieve the desired therapeutic outcomes since photosensitizers Ce6 have strong hydrophobic properties and are not taken up efficiently by periodontal pathogenic bacteria. Li et al. designed a nanosystem to improve Ce6 solubility and enhance its bacterial adsorption by promoting its interaction with negatively charged cell walls and penetration through cell membranes [76]. They first hydrophilically-modified Ce6 via conjugation with TAT peptide, a cationic cell-penetrating peptide (TAT-Ce6). Then, TAT-Ce6 was loaded with the antibiotic agent tinidazole to prepare self-assembled nanoparticles (TAT-Ce6/TDZ NPs) to achieve synergistic anti-periodontitis effects by combining PDT and antibiotic therapy (Fig. 4B). TEM image showed that TAT-Ce6/TDZ NPs had a regular spherical shape and exhibited a more compact inner structure. The particle size of TAT-Ce6/TDZ NPs was ~ 146.2 nm, and the zeta potential was approximately + 40.1 mV, which confirmed the surface distribution of the positively charged TAT peptide. The UV absorption of ABDA attenuates when ABDA is decomposed by the ROS produced in the sample solution, and the degree of attenuation is positively correlated with the ROS generation level. The results showed that the attenuation rate of ABDA absorption in the solution of TAT-Ce6/TDZ NPs was much faster than that of free Ce6 during 20 min of laser irradiation, indicating that TAT-Ce6/TDZ NPs had a much higher PDT efficiency. The zeta potentials of Pg were increased from − 11.2 to + 5.86 mV after 1 h of incubation with TAT-Ce6. The above results indicated that TAT-Ce6 significantly promoted the penetration of the bacterial cell membrane through the TAT peptide. TAT-Ce6/TDZ NPs and TAT-Ce6 exhibited much stronger bacterial killing activity, owing to their more efficient absorption by the plaque biofilms via the mediation of TAT peptide. More importantly, TAT-Ce6/TDZ NPs exhibited much stronger bacterial killing activity than TAT-Ce6 NPs with laser irradiation, further confirming their synergistic antibacterial efficacy through combining PDT and antibiotic therapy.

Indocyanine green (ICG), a photosensitizer with PDT properties, has been approved for clinical use by the US Food and Drug Administration [77]. Nagahara et al. first explored PDT of photosensitizer indocyanine green, which has high absorption at a wavelengths of 800–805 nm [78]. They designed ICG-loaded PLGA nanospheres coated with chitosan (ICGNano/c) and explored the PDT of ICGNano/c in Pg. The study showed that ICG-Nano/c with low-level diode laser (0.5 W, 805 nm) irradiation showed a PDT-like effect, which might be useful for potential photodynamic periodontal therapy. Recently, combined treatment with PTT and PDT has further improved the efficiency of periodontitis treatment. However, due to its negative charge and water solubility, ICG has difficulty passing through bacterial cell membranes. To address this problem, Shi and his colleagues incorporated it into positively charged polycationic brush nanoparticles (sPDMA@ICG NPs) (Fig. 4C) [79]. CD-Br was synthesized by esterifying β-cyclodextrin with 2-bromoisobutyryl bromide via an esterification reaction. Next, star-shaped polycationic brush poly (2-(dimethyl amino) ethyl methacrylate) was synthesized by an atom transfer radical polymerization reaction using CD-Br as an initiator. Finally, sPDMA@ICG NPs loaded with ICG were prepared by the nanometer precipitation method. The average particle size of sPDMA@ICG NPs was 206 nm and the zeta potential was approximately + 18.4 mV. On the one hand, the temperature of the sPDMA@ICG NPs solution was increased from 22 to 55 °C after irradiation with an 808 nm laser (2 W/cm2), which reflects an excellent PTT performance. On the other hand, sPDMA@ICG NPs also exert PDT properties. The results suggested that sPDMA@ICG NPs can produce ROS after laser irradiation, as detected by SOSG. Confocal microscopy images show that sPDMA@ICG NPs are effectively accumulate in bacterial cells after the administration of sPDMA@ICG NPs. TEM images showed that sPDMA@ICG NPs were clearly visible on the surface of Pg, and that the bacterial film ruptured and bacterial cells disintegrated after laser irradiation (Fig. 4D). In addition, sPDMA@ICG NPs with laser irradiation reduced the growing area of plaque biofilms derived derive from a rat model of periodontitis (Fig. 4E). After sPDMA@ICG NPs administration and laser irradiation, temperature and ROS levels were increased in rats with periodontitis, indicating that sPDMA@ICG NPs exert synergistic PTT and PDT effects in vivo (Fig. 4F).

Immunomodulatory nanotherapeutic strategies

In periodontitis, the presence of plaque microorganisms and their products can activate the host immune response [80]. Local host immune overreaction then, leads to increased inflammation and disruption of homeostasis, exacerbating periodontium lesions. Most tissue damage within periodontitis is caused by the host immune response rather than directly by the infecting microorganism [81, 82]. Therefore, in terms of therapeutic strategies, suitable immunomodulatory targets can be screened to modulate the host immune system to mitigate the inflammatory response. Recently, many nanosystems have been designed to modulate the function of immune cells and inflammation-associated cytokines to alleviate periodontal inflammation, and these nanosystems have achieved excellent therapeutic results both in vitro and in vivo (Table 2).

Table 2 Immunomodulatory nanotherapeutic strategies for periodontitis treatment
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Remodeling macrophage polarization

In the immune system, immune cells such as macrophages play an important role as the host's first line of defenses against microorganisms. When induced by different factors, macrophages polarize and develop different phenotypes, such as M1 and M2, both of which are involved in regulating the immune response [83]. M1-type macrophages produce the cytokines IL-6 and TNF-α, which promote the inflammatory response [84, 85]. M2 macrophages can be further classified into alternatively activated macrophages (M2a), type 2 macrophages (M2b), deactivated macrophages (M2c), and M2-like macrophages (M2d) by different stimuli and transcription levels [86, 96]. IL-17 has been shown to boost RANKL expression while inhibiting OPG expression in periodontal ligament cells, which might explain why Th17 cells promote alveolar bone loss [95]. However, Tregs can suppress the host immune response in equilibrium with Th17 cells in the periodontium [97, 98]. To date, no drug/nanosystem has been reported to directly regulate the Th17/Treg cells balance, but exosomes derived from periodontal ligament stem cells have been found to have the potential to regulate Th17/Treg cells.

Zhang et al. found that exosomes derived from mesenchymal stem cells (3D-exos) could regulate Th17/Tregs cell balance [99]. Notably, replacing the traditional 2D culture system with a 3D system could increase exosome production. The average particle size of the 3D-exos was 50–200 nm. A significant Th17 reduction and Treg elevation were observed in the periodontium after treatment with 3D-exos in periodontitis mice. Gene Ontology analysis showed that differentially expressed genes in 3D-exo-treated mice with periodontitis were enriched for T-cell chemotaxis. These results suggested that 3D-exos can further regulate Th17/Tregs cells in a periodontitis mice model. Furthermore, RNA-seq and TargetScan results indicated that miR-1246 is the most differentially expressed miRNA in 3D-exo, which targets Nfat5. Nfat5 is a key factor that mediates Th17 cell polarization in a sequence-dependent manner. Therefore, 3D-exo suppresses Th17 cell differentiation by miR-1246 through downregulation of Nfat5 gene expression.

Zheng et al. investigated the effect of exosomes from periodontal membrane stem cells (PDLSC-exos) on Th17/Treg balance [100]. The expression of the Th17-related transcription factor RAR-related orphan receptor C was upregulated and the Treg-related transcription factor forkhead Box P3 was down-regulated in periodontitis patients. This means that the Th17/Treg ratio is unbalanced in patients with periodontitis. The results showed lower Th17-related CD4+/IL‐17+ expression and increased Treg-related CD4+CD25+FOXP3+ expression after treatment of PDLSC-exos in CD4+ T cells, confirming the regulatory effect of PDLSCs-exos on the Th17/Treg balance. In addition, the mechanistic results showed that PDLSC-exos transfer miR-155-5p into CD4+ T cells, which in turn regulates the expression of histone deacetylase protein in CD4+ T cells, thus affecting the Th17/Treg homeostasis. Therefore, miR-155-5p may be a promising target for the treatment of immune imbalance in periodontitis. In summary, exosomes are a potential nano drug delivery system to regulate the balance of Th17 and Treg cells, and their potential in the treatment of periodontitis needs to be further explored.

Regulating pro-/anti-inflammatory cytokine secretion

Inflammatory cytokines secreted from immune or tissue cells are key regulators of the immune response process, and pro-/anti-inflammatory cytokine imbalance is an important factor in the aggravation of periodontitis [37]. Cytokines, such as IL-1β, IL-6 and TNF-α, activate inflammation-related transcription factors or activate related signaling pathways, thereby accelerating the process of periodontitis. The anti-inflammatory cytokines of IL-10, TGF-β and IL-11, downregulate the expression levels of pro-inflammatory factors, protect the periodontium and inhibit the development of periodontitis [101,102,103]. It is extremely important to modulate pro-/anti-inflammatory cytokine secretion for restore immune balance in periodontitis treatment.

Li et al. prepared baicalin and baicalein-loaded mesoporous silica nanoparticles (Nano-BA and Nano-BE) to regulate inflammatory cytokine secretion [104]. The mesoporous silica nanoparticles were modified by 3-aminopropyl-triethoxy silane. An inflammation cell model was established by primary human gingival epithelial cells pretreated with IL-1β stimulation. Nano-BA and Nano-BE downregulated cytokines involved in the immune inflammatory response. Among them, epithelial cell-derived neutrophil-activating peptide 78, monocyte chemoattractant protein-1, and IL-8 function as chemokines leading to inflammation or tissue damage, while granulocyte colony-stimulating factor and granulocyte–macrophage colony-stimulating factor stimulate the differentiation and proliferation of hematopoietic stem cell immune cells.

In another study, Polydopamine nanoparticles (PDA NPs) were synthesized via self-polymerization with dopamine hydrochloride and a solution containing NH4OH and ethanol [105]. PDA NPs effectively reduce the levels of TNF-α and IL-1β inflammatory mediators. After PDA NPs treatment in mice, the cytokine levels of TNF-α, IFN -γ, and IL-1β in serum recovered to normal values. Moreover, all the levels of alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase (ALP) were also in the reference normal ranges. Notably, PDA NPs efficiently reduced the level of ROS in LPS-induced local high fluorescence signals. The above results suggest that reducing ROS levels may help to regulate inflammatory cytokine levels during periodontitis treatment.

Periodontium regeneration nanotherapeutics strategies

The periodontium consists of the gingiva, periodontal ligament, alveolar bone and cementum, which provide physical and mechanical support for the teeth [106, 107]. Severe periodontitis leads to the loss of periodontal attachment, which is one of the major causes of tooth loss in adults. Therefore, the main goal of periodontitis treatment is to reduce the destruction of the periodontium, finally achieving periodontium regeneration. In recent years, researchers have proposed a series of advanced nanotherapeutic strategies to achieve periodontium regeneration by regulating cell differentiation and disturbing osteoclastogenesis (Table 3).

Table 3 Periodontium regeneration nanotherapeutic strategies for periodontitis treatment
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Promoting periodontal membrane stem cell differentiation

Periodontal membrane stem cells (PDLSCs), a subpopulation of mesenchymal stem cells, have self-renewal and immunomodulatory properties [108]. Moreover, PDLSCs can specifically repair the damaged periodontium [109]. PDLSCs can differentiate into fibroblasts, osteoblast-like cells and dental osteoclast-like cells to generate connective and dental osteoid tissue by nanomedicine (Fig. 6A) [110]. Therefore, regulating the differentiation of PDLSCs is a promising strategy for periodontium repair.

Fig. 6
figure 6

A PDLSCs through self-renewal, differentiating into osteoblasts and fibroblasts and regulating the host immune response to maintain the periodontal homeostasis. Reprinted with permission from Ref. [34] Copyright Oxford University Press. B Schematic illustration of M2-Exos promoting osteogenic differentiation of bone marrow stromal cells and inhibiting osteoclast formation of bone marrow-derived macrophages. Reprinted with permission from Ref. [125] Copyright Springer Nature

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AuNPs promote the proliferation of human periodontal membrane stem cells via the classical Wnt/β-linked protein signaling pathway [111]. On this basis, Zhang et al. further investigated the potential of AuNPs to promote osteogenic differentiation of PDLCs [173]. In addition, the smart hydrogel can control release nanomedicines through the stimuli-responses including ROS, pH, light, enzymes, etc. MZ@PNM was integrated with chitosan/sodiumβ-glycerophosphate system for pH-responsive release properties due to the remaining amino groups on chitosan matrix. The hydrogel structure was significantly collapse after incubation at pH 4.0 than at pH 7.4, which could release the nanoparticles in the acidic periodontal environment [137].

In addition, bio-sponges with porous structures have ideal loading properties, biocompatibility and biodegradability, which gain attention in the field of hemostasis and wound healing. Wang's group prepared bio-sponges based on carboxymethyl chitosan/ poly-gamma-glutamic acid/platelet-rich plasma that adhere and coagulate red blood cells to accelerate blood clotting via releasing epidermal growth factor and vascular endothelial growth factor [174]. In the field of periodontitis treatment, bio-sponge platforms are absorbable and relatively inert during bone regeneration. Mesenchymal stem cell exosome-loaded collagen sponge promoted newly-formed bone and periodontal ligament regeneration by increasing periodontal ligament cell migration and proliferation [175].

Electrets have attracted widespread interest in bone regeneration and drug delivery due to the great performance in endogenous electrical stimulation for enhancing cell proliferation and differentiation [176]. Yu et al. designed an electret-based host-coupled biological nanogenerator through electrical stimulation to increase cytoplasmic calcium ions to activate osteogenic differentiation. The result showed that electret significantly promoted the osteogenic differentiation of bone marrow mesenchymal stem cells in vitro and bone regeneration in vivo [177]. The development of nanocomposite delivery systems utilizing the advantages of charge retention and high surface charge density of electrets nano-materials such as ZnO and SiO2, may be a potential therapeutic strategy for the treatment of periodontitis.

Opportunities of periodontitis comorbidities treatment

Periodontitis is associated with diabetes, rheumatoid arthritis, Alzheimer's disease, hypertension, inflammatory bowel disease, and even autoimmune diseases and cancer (Fig. 11) [178,179,180]. Therefore, nanodelivery systems also have promising applications in the treatment of periodontitis with comorbidities. For instance, there is a bidirectional association between periodontitis and diabetes [181]. Periodontitis may increase the prevalence of diabetes and affect the effective control of blood glucose [182, 183]. On the other hand, metabolic disorders in diabetic patients lead to excessive production of ROS, which has a damaging effect on alveolar bone. The damage to periodontal tissue in diabetic patients with periodontitis was more destructive than that in patients with periodontitis alone. To address this problem, Zhao et al. developed a ROS-responsive drug delivery system loaded with both doxycycline and metformin that worked effectively in periodontitis with diabetes [184]. Wang et al. prepared injectable nano-hydrogels using mesoporous silica nanoparticles incorporating poly(d, l-lactide)-block-poly(ethylene glycol)-block-poly(d, l-lactide) to model the mesenchymal stem cells "recruitment-osteogenic" cascade for periodontal bone regeneration [185]. Nanotherapeutic strategies will provide more opportunities for the treatment of periodontitis complications.

Fig. 11
figure 11

Periodontitis and associated inflammatory comorbidities. Reprinted with permission from Ref. [186] Copyright Springer Nature

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Nanotherapeutic potential of natural active ingredients

Antibiotics and non-steroidal anti-inflammatory agents have potential problems in the treatment of periodontitis including drug resistance, dysbacteriosis and gastrointestinal adverse effects. Natural components derived from natural sources are currently attracting interest from researchers. Natural ingredients with proven therapeutic effects on periodontitis include quercetin, resveratrol, baicalin, curcumin, etc. [187].

Quercetin has a potential protective effect against chronic inflammation-related periodontitis by suppressing the Akt/AMPK/mTOR pathway [188]. In another study, quercetin was found to reduce alveolar bone loss by inhibiting inflammation in periodontitis rats [189]. Resveratrol protects against periodontitis-induced tissue damage by augmenting HO-1 via Nrf2-mediated signaling [190]. Curcumin significantly reduced the expression of TNF-α and IL-6 by inhibiting the phosphorylation of p38 MAPK and reducing the inflammatory response in macrophages [191]. Plumbagin down-regulating the mRNA expression of the pro-inflammatory cytokines TNF-α, IL-1β and IL-6 in periodontium, thereby retarding the development of inflammation [192].

Natural ingredients have achieved excellent experimental results in the treatment of periodontitis. However, most of the natural ingredients have poor solubility and safety problems. In addition, little is known about the in vivo pharmacokinetic studies of natural active ingredients, which limits the clinical translation of natural active ingredients in the treatment of periodontitis. The use of advanced nanodrug delivery systems is expected to solve the problems of drug formation of natural ingredients in the future.

Conclusion

The in-depth study of pathogenesis and the development of nanomaterial engineering promote the development of nanotherapeutic strategies for periodontitis. The diverse physicochemical properties and targeting properties of nanodelivery systems create a favourable platform for drug delivery to treat periodontitis. In this article, we review the nanotherapeutic strategies for periodontitis to provide inspiration for future advances in periodontitis treatment and innovations in the design of nanodelivery systems. Overall, nanotherapeutics have shown great potential at preclinical levels, but their clinical performance remains to be evaluated. More work is needed to refine the development of novel nanotherapeutic strategies. We believe that nanotherapeutic strategies will soon provide new opportunities for the treatment of periodontitis, thereby alleviating patient suffering and the medical burden on society.