1. Introduction

Periodontitis is a chronic inflammatory disease induced by plaque biofilms, characterized by progressive destruction of tooth-supporting tissues, including the gingiva, periodontal ligament, cementum and alveolar bone^[1-4]. As the sixth most prevalent chronic inflammatory disease worldwide, it affects approximately 10-15% of the global population and remains a leading cause of tooth loss in adults^[5-7]. Clinical manifestations include gingival bleeding, periodontal pocket formation, alveolar bone resorption, and eventual tooth loosening or loss^[8-10]. Moreover, periodontitis is closely associated with various systemic diseases, including type 2 diabetes, cardiovascular disease, Alzheimer’s disease, and rheumatoid arthritis^[11-14]. Current standard treatments, including mechanical debridement, antibiotic therapy, and surgical intervention, are limited by incomplete bacterial eradication, increasing antibiotic resistance, and insufficient capacity to promote periodontal tissue regeneration^[15-18]. Consequently, innovative therapeutic strategies that effectively regenerate periodontal tissue are urgently needed.

Mitochondrial dysfunction is a pivotal pathogenic driver of periodontitis. Under physiological conditions, mitochondria generate adenosine triphosphate (ATP) via oxidative phosphorylation (OXPHOS), which is essential for maintaining periodontal tissue homeostasis, including cell differentiation, mineralization, and regeneration^[19,20]. In periodontitis, multiple periodontal cell types exhibit mitochondrial abnormalities, including decreased membrane potential and elevated reactive oxygen species (ROS) levels, which impair mitochondrial quality control and perpetuate inflammation^[20,21]. Specifically, inflammatory stimuli may trigger calcium overload, excessive mitochondrial reactive oxygen species (mtROS) production, and mitochondrial DNA (mtDNA) release, thereby driving the activation of NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, a key event in the periodontal inflammatory cascade^[22]. Simultaneously, inflammation-induced glycolytic metabolism reduces ATP production and further elevates ROS levels^[23], leading to oxidative stress and ultimately irreversible periodontal tissue damage^[23,24].

Mitochondrial dysfunction inhibits periodontal repair while accelerating disease progression. For example, mitochondrial dysfunction undermines antibacterial defense by impairing the bactericidal activity of neutrophils and macrophages^[25,26]. Additionally, mitochondrial dysfunction drives macrophages toward a pro-inflammatory M1 phenotype while suppressing the reparative M2 phenotype, thereby perpetuating inflammation^[27]. During osteogenesis, mitochondria are indispensable for the osteogenic differentiation of stem cells as they coordinate oxidative stress and autophagy to transduce osteogenic signaling pathways^[28,29]; however, excessive ROS may disrupt redox homeostasis, triggering osteoblast ferroptosis and impairing bone formation^[30]. Furthermore, mitochondrial dysfunction hinders endothelial cell (EC) proliferation, migration and tube formation, thereby impairing angiogenesis and tissue repair^[31,32]. Therefore, it is necessary to design functional biomaterials that modulate mitochondrial function to realize periodontal tissue regeneration.

To date, various mitochondria-regulating biomaterials have been developed for periodontitis therapy (Figure 1). In this review, the fundamental characteristics of mitochondrial dysfunction in periodontitis and its impact on key physiological processes are outlined. Subsequently, recent advances in mitochondria-regulating biomaterials for periodontitis therapy are highlighted. Finally, current challenges and future perspectives regarding clinical translation are discussed. This review provides a brief overview of mitochondria-regulating biomaterials for periodontitis therapy, aiming to offer a basic reference for researchers entering this field.

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Figure 1. Design and therapeutic mechanisms of mitochondria-regulating biomaterials for periodontitis. Created in BioRender. Dwad, D. (2026) https://BioRender.com/fs7akdh. PDLSC: periodontal ligament stem cell; ROS: reactive oxygen species; OXPHOS: oxidative phosphorylation; mTOR: mammalian target of rapamycin; NAD: nicotinamide adenine dinucleotide.

2. Mitochondrial Dysfunction in Periodontitis

Pathogens such as Porphyromonas gingivalis (P. gingivalis) induce mitochondrial dysfunction, perturb metabolic homeostasis, and promote ROS production, thereby exacerbating periodontal inflammation and impairing tissue repair^[33]. In this section, mitochondrial dysfunction of major cell types is introduced (Figure 2).

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Figure 2. Cell-type-specific mitochondrial dysfunction and intercellular crosstalk in periodontitis. Created in BioRender. Dwad, D. (2026) https://BioRender.com/rtzmsgr. GF: gingival fibroblast; PDLC: periodontal ligament cell; PDLSC: periodontal ligament stem cell; NET: neutrophil extracellular trap; TNF-α: tumor necrosis factor-α; IL-1β: interleukin-1β.

2.1 Immune cells

Periodontal biofilms release virulence factors that induce metabolic reprogramming in local immune cells, driving sustained production of pro-inflammatory cytokines and ROS that lead to gingival tissue degradation and alveolar bone resorption^[34]. Within this inflammatory milieu, mitochondrial dysfunction directly shapes the behavior of immune cells, particularly macrophages and neutrophils.

Macrophages, as a central component of innate immunity, play a critical role in periodontitis, where their polarization drives its pathogenesis^[35]. Mitochondrial metabolic state shapes macrophage polarization, with M1 macrophages relying on enhanced glycolysis alongside impaired tricarboxylic acid (TCA) cycle and OXPHOS for rapid pro-inflammatory responses, whereas M2 macrophages depend on an intact TCA cycle and enhanced OXPHOS for anti-inflammatory cytokine production^[36-38]. Besides, mitochondrial quality control also determines macrophage fate. Enhanced mitophagy promotes polarization towards M2 macrophages and attenuates periodontitis^[39], while excessive Drp1 activation drives mitochondrial fragmentation and membrane potential loss in the P. gingivalis-induced periodontitis macrophage model, with Drp1-HK1 binding promoting excessive mitochondrial permeability transition pore (mPTP) opening and releasing mtDNA, mtROS, and other toxic substances into the cytoplasm, thereby activating the NLRP3 inflammasome to induce inflammatory damage^[40].

Neutrophils, the most abundant innate immune cells in periodontal tissue, are essential for maintaining periodontal immune homeostasis^[41]. In periodontitis, mitochondrial dysfunction in neutrophils manifests as excessive mtROS production, which promotes the release of mitochondrial neutrophil extracellular traps (NETs)^[42]. Such dysfunction may further impair migration ability and delay inflammation resolution, collectively aggravating tissue damage^[43].

2.2 Gingival fibroblasts

Gingival fibroblasts (GFs) are the predominant cells in gingival connective tissue, serving as sentinel cells for innate immune responses and major regulators of extracellular matrix (ECM) remodeling^[44]. In periodontitis, GFs exhibit aberrant mitochondrial structure and function compared with periodontally healthy individuals^[45]. Mechanistically, lipopolysaccharide (LPS) stimulation inhibits mitophagy in GFs, thereby activating the NLRP3 inflammasome and mediating pyroptosis^[46]. In parallel, LPS derived from P. gingivalis elevates ROS levels and promotes the opening of mPTP by suppressing pyruvate dehydrogenase kinase 2 (PDK2) expression, leading to mtDNA release^[47], which activates the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway and PANoptosis^[48].

2.3 Periodontal ligament cells and stem cells

Periodontal ligament cells (PDLCs), also known as periodontal ligament fibroblasts (PDLFs), are the most abundant cells in the periodontal ligament and play a pivotal role in periodontitis progression via inflammation, tissue repair, and periodontal regeneration^[20]. Excessive ROS induces mitochondrial dysfunction in PDLCs, characterized by elevated mtROS, reduced mitochondrial membrane potential and ATP levels, and increased Drp1-related mitochondrial fission, ultimately leading to apoptosis of PDLCs^[49,50].

Periodontal ligament stem cells (PDLSCs), the main mesenchymal stem cells (MSCs) in the periodontal ligament, play a critical role in immune regulation and can differentiate into various cell types to repair damaged periodontal tissue^[51]. In periodontitis, impaired mitophagy leads to the accumulation of damaged mitochondria, thereby compromising the osteogenic capacity of PDLSCs^[52]. In parallel, periodontal inflammation induces mitochondrial dysfunction that impairs cementoblastic differentiation^[53] and reduces ATP production and activates apoptotic signaling, ultimately diminishing the regenerative capacity of PDLSCs^[54].

2.4 Bone-related cells

Alveolar bone resorption is a central pathological hallmark of periodontitis, fundamentally reflecting an imbalance between bone formation and bone resorption^[55]. Mitochondrial dysfunction impairs osteoblast-mediated bone formation while enhancing osteoclast-mediated bone resorption, collectively driving alveolar bone loss.

Osteoblasts are the principal bone-forming cells residing in the alveolar bone^[56]. In periodontitis, excessive ROS, resulting from mitochondrial dysfunction, inhibit the differentiation and mineralization of osteoblasts by suppressing the Wnt/β-catenin, mitogen-activated protein kinase (MAPK), and PI3K/Akt pathways^[57], and mtROS-induced mitochondrial impairment ultimately leads to osteoblast death^[58].

Osteoclasts serve as the key effector cells of alveolar bone resorption in periodontitis^[59]. PTEN-induced kinase 1 (PINK1)-mediated mitophagy regulates osteoclast formation, differentiation, and function during alveolar bone resorption in periodontal disease^[60]. In periodontitis, alveolar bone destruction is accompanied by decreased PINK1 expression and an increase in osteoclast number^[61]. Consistently, PINK1 deficiency significantly increases the number of tartrate resistant acid phosphatase (TRAP) positive osteoclasts and exacerbated alveolar bone loss^[62]. Besides, ROS overproduction promotes osteoclast differentiation by activating transient receptor potential melastatin 2 (TRPM2), eventually leading to bone degradation in periodontitis^[63].

2.5 Intercellular crosstalk and synergistic effects

Mitochondrial dysfunction in periodontitis is multicellular and involves intercellular crosstalk among immune cells, stem cells, and bone cells. For example, in periodontitis, mitochondria-rich extracellular vesicles (EVs) derived from inflammatory macrophages disrupt mitochondrial homeostasis in bone marrow mesenchymal stem cells (BMSCs) by upregulating lipocalin 2 (LCN2), which induces OMA1 degradation and OPA1 accumulation, ultimately inhibiting osteogenesis and exacerbating alveolar bone resorption^[21], demonstrating that mitochondrial stress can be transmitted between cell types, impairing the function of target cells and compromising tissue repair. Mitochondrial dysfunction in periodontitis is a transmissible pathological signal rather than a cell-intrinsic defect, which propagates through intercellular crosstalk to form a synergistic network that amplifies tissue destruction.

Moreover, mitochondrial repair in one cell type may produce synergistic therapeutic effects by influencing others. For instance, transplanting M2 macrophage-derived mitochondria into PDLSCs under inflammatory conditions restored mitochondrial function, ultimately promoting osteogenic differentiation and periodontal bone regeneration^[64]. Similarly, a sericin-based dual-module microsphere system (SeHA@EC) attenuated intracellular ROS levels, stabilized mitochondrial membrane potential in macrophages, thereby promoting M2 polarization and subsequently enhancing the osteogenic differentiation of PDLSCs^[65]. These findings demonstrate that regulating mitochondrial function in one cell type can influence other cell types via intercellular crosstalk, thereby achieving synergistic therapeutic effects. Overall, mitochondria may serve as a shared therapeutic target across multiple cell types in periodontitis.

3. Impact of Mitochondrial Dysfunction on Key Physiological Processes

Mitochondria regulate multiple crucial physiological processes involved in periodontal tissue regeneration, including generating mtROS for antibacterial defense, orchestrating immune responses to resolve inflammation, supporting osteogenic differentiation, and promoting EC proliferation and migration for angiogenesis. However, mitochondrial dysfunction impairs these physiological processes, leading to persistent infection, unresolved inflammation, and compromised tissue regeneration.

3.1 Antibacterial defense

Mitochondria are critical for antibacterial functions of innate immune cells. Physiologically, mitochondria provide ATP to support macrophage phagocytosis^[66], produce mtROS as direct antimicrobial agents^[67], and sense bacterial metabolites such as lactate to trigger NETs release^[68], thereby contributing to antibacterial defense.

However, periodontal pathogens like P. gingivalis hijack mitochondrial homeostasis to subvert the host antibacterial defenses. In neutrophils, P. gingivalis outer membrane vesicles (OMVs) stimulation increases glucose uptake and lipid droplet accumulation, reduces lactate release, and lowers mitochondrial mass and membrane potential, which in turn enhances P. gingivalis internalization and intracellular bacterial survival, reflecting an impaired extracellular antibacterial response^[69]. Similarly, in macrophages, P. gingivalis outer membrane vesicles (OMVs) promote a metabolic shift toward glycolysis and disrupt mitochondrial function and the TCA cycle, thereby activating pro-inflammatory cytokine production, inflammasome signaling, and pyroptosis and ultimately weakening their antibacterial capacity^[70]. P. gingivalis also elicits a mitochondrial stress response that drives mtDNA release, which in turn engages Z-DNA binding protein 1 (Zbp1) to amplify downstream PANoptosis signaling^[71]. Together, these mechanisms establish mitochondrial dysfunction as a central node that impairs cellular bioenergetics and activates the cGAS-STING pathway or NLRP3 inflammasome, thereby promoting pro-inflammatory cytokine secretion and further compromising immune cell function^[72]. Consequently, restoring mitochondrial homeostasis represents a promising strategy to rescue antibacterial capacity. Indeed, baicalin induces Drp1-dependent mitochondrial biogenesis, enhances mitochondrial membrane potential and ATP levels, and reduces mtROS production in macrophages, thereby promoting antibacterial responses during Staphylococcus aureus infection^[73].

3.2 Anti-inflammation and immunomodulation

Mitochondria regulate immune responses and determine the activation, differentiation, and effector functions of immune cells^[74-76]. Under physiological conditions, mitochondria maintain immune homeostasis. However, when mitochondrial function is impaired, immune homeostasis is disrupted and inflammation is exacerbated. Specifically, mitochondrial dysfunction drives a metabolic shift toward glycolysis, sustaining the pro-inflammatory M1 phenotype and impairing M1-to-M2 repolarization, thereby exacerbating periodontal inflammation^[75,77,78]. Mitochondrial dysfunction also induces mtDNA release, which triggers excessive inflammation by activating the cGAS-STING pathway^[79]. Mitochondrial dysfunction further triggers excessive mitochondrial fission, driving M1 macrophage polarization and aggravating periodontal inflammation^[80]. Overall, mitochondrial dysfunction sustains a pro-inflammatory state in periodontal tissues, impairing inflammation resolution and tissue repair.

3.3 Osteogenesis

Mitochondria are the primary source of ATP and critically regulate stem cell fate during bone regeneration^[81]. During osteogenic differentiation of BMSCs, mitochondrial metabolism shifts from glycolysis to OXPHOS to support ATP production for the high energy demands of osteogenesis^[82,83]. In addition, mitochondrial dynamics regulate osteogenesis, with moderate fission promoting osteogenesis and enhanced fusion suppressing it^[84].

However, mitochondrial dysfunction suppresses osteogenesis through distinct mechanisms across cell types. In BMSCs, mitochondrial dysfunction promotes cellular senescence and impairs osteogenesis via impaired mitophagy, energy metabolism disorders, and fusion–fission imbalance^[85]. In MC3T3-E1 cells, mitochondrial dysfunction disrupts osteogenic differentiation via fusion-fission disorders^[86]. In osteoblasts, mitochondrial dysfunction triggers cell death and functional impairment via elevated mtROS^[58]. Therefore, restoring mitochondrial function represents a viable strategy to promote osteogenesis and accelerate periodontal healing.

3.4 Angiogenesis

Mitochondria supply ATP to support EC proliferation, migration, and survival and sense hypoxia via complex III to generate transient mtROS, which stabilizes HIF-1α and upregulates vascular endothelial growth factor (VEGF)^[87,88], while also activating endothelial nitric oxide synthase (eNOS) to promote EC proliferation and angiogenesis^[89].

However, mitochondrial dysfunction results in excessive mtROS production, dysregulated mitochondrial dynamics, and disrupted Ca²⁺ homeostasis. Sustained mtROS generation produces ONOO^- and inactivates MnSOD via nitrotyrosine formation, reducing mitochondrial membrane potential and thereby inhibiting EC proliferation^[89,90]. Concurrently, excessive mitochondrial fission reduces mitochondrial mass, further compromising EC proliferation^[91], while dysregulated Ca²⁺ signaling additionally suppresses EC migration and angiogenesis^[92]. Collectively, mitochondrial dysfunction impairs EC proliferation, migration, and angiogenesis, underscoring the necessity of restoring mitochondrial function to preserve endothelial homeostasis. For example, L-arginine protects endothelial cells from ROS insult by promoting PINK1/Parkin- and BCL2 and adenovirus E1B 19 kDa-interacting protein 3 (BNIP3)-dependent mitophagy^[93].

4. Application of Mitochondria-Regulating Biomaterials in Periodontitis

Mitochondrial dysfunction underlies the initiation and progression of periodontitis, triggering excessive ROS production, NLRP3 inflammasome activation, and the release of pro-inflammatory cytokines while impairing ATP synthesis. Accordingly, various mitochondria-regulating biomaterials including anti-inflammatory and immunomodulatory, osteogenic, and multifunctional biomaterials have been engineered to restore mitochondrial homeostasis and promote periodontal tissue regeneration.

4.1 Anti-inflammatory and immunomodulatory mitochondria-regulating biomaterials

Mitochondrial dysfunction is increasingly recognized as a common upstream event of inflammatory cell activation, driving persistent inflammation and tissue destruction, and therefore, biomaterials that regulate mitochondrial function can suppress the activation of multiple inflammatory cells, ultimately promoting periodontal tissue regeneration. Table 1 summarizes representative biomaterials with anti-inflammatory and immunomodulatory functions.

Nanomaterials have attracted considerable attention as mitochondria-regulating platforms owing to their nanoscale dimensions, tunable surface properties, and targeting potential. Antioxidant-loaded nanocarriers, typically liposomes or polymeric nanoparticles, encapsulate small-molecule antioxidants to avoid rapid metabolism and facilitate mitochondria-specific delivery, thereby scavenging mtROS and enhancing mitophagy, which in turn alleviates periodontal inflammation. Mitoquidone mesylate (MitoQ), a well-established mitochondria-specific antioxidant^[94], is limited by its poor water dispersion and stability, and gastrointestinal side effects^[95,96]. To overcome these drawbacks, MitoQ was encapsulated in poly (lactic-co-glycolic acid) (PLGA)-poly (ethylene glycol) (PEG) nanoparticles modified with targeted peptides (MPPT NPs) and subsequently integrated into a ROS-responsive hydrogel (MTP hydrogel) that targeted mitochondria, scavenged ROS, and repaired damaged mitochondria, resulting in a bone volume fraction (BV/TV) 1.5 times higher than previously reported values^[97]. However, the long-term safety of exogenous antioxidants remains a concern. As an alternative, coenzyme Q₁₀ (CoQ₁₀), an endogenous antioxidant^[98], was encapsulated into mitochondria-targeted liposomes (CoQ₁₀ mitochondria-targeted liposome (MLip)) and further incorporated into an ROS-responsive hydrogel (CoQ₁₀ MLip/ROS-responsive hydrogel (Gel)), which scavenged ROS, rejuvenated mitochondrial energy metabolism, and restored mitochondrial integrity, ultimately alleviating periodontal inflammation (Figure 3a)^[24].

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Figure 3. (a) Schematic illustration of the design of CoQ₁₀-MLip/Gel and its mechanism diagram for the periodontal treatment. Reproduced from reference^[24]. CC BY 4.0; (b) Schematic diagram of the design and mitochondria-centered redox modulation mechanism of TC/pSeSe nanocomposite for restoring alveolar bone homeostasis in periodontitis. Reproduced from reference^[99]. CC BY 4.0; (c) Schematic illustration of the design of FIS-CDs and their anti-inflammatory and antioxidant mechanisms in periodontal diseases. Reproduced from reference^[101]. CC BY 4.0; (d) Schematic diagram of synthesis and action mechanism of mitochondria-targeted TPP-SAT for periodontitis treatment. Reproduced from reference^[100]. CC BY 4.0. CoQ₁₀: coenzyme Q₁₀; MLip: mitochondria-targeted liposome; Gel: ROS-responsive hydrogel; TC: triphenylphosphine chitosan; pSeSe: ROS-responsive diselenide-containing copolymer nanoparticle; FIS-CDs: FIS-derived carbon dots; FIS: fisetin; SOD: superoxide dismutase; CAT: catalase; ROS: reactive oxygen species; STING: stimulator of interferon genes; TPP: triphenylphosphine; cGAS: cyclic GMP-AMP synthase; ATP: adenosine triphosphate; TNF-α: tumor necrosis factor-α; IL-1β: interleukin-1β; SIRT3: SUMOylation of sirtuin 3; NLRP3: NOD-like receptor family pyrin domain containing 3; mtROS: mitochondrial reactive oxygen species; mtDNA: mitochondrial DNA; Nrf2: nuclear factor erythroid 2-related factor; NF-κB: nuclear factor-kappa B; PLGA: poly (lactic-co-glycolic acid); GPX4: glutathione peroxidase 4; GSH: glutathione; ACSL4: acyl-CoA synthetase long-chain family member 4; IFN: interferon; TGF-β: transforming growth factor-β; IRF3: interferon regulatory factor 3; cGAMP: cyclic guanosine monophosphate–adenosine monophosphate; RANKL: receptor activator of nuclear factor-κB ligand.

Stimuli-responsive nanomaterials scavenge ROS via responsive degradation and subsequent release of bioactive factors, thereby breaking the vicious cycle of ROS, inflammation and hypoxia in periodontitis. For example, a redox-responsive nanocomposite (TC/pSeSe) consisting of a ROS-responsive diselenide-containing copolymer nanoparticle (pSeSe) core and a triphenylphosphine (TPP)/chitosan (TC) coating was developed to achieve mitochondrial targeting, mucosal adhesion, and antibacterial functions (Figure 3b)^[99]. Upon oxidative stress, diselenide bonds broke to release selenium, which scavenged ROS and suppressed mtDNA-mediated cGAS-STING signaling, alleviating periodontal inflammation and promoting alveolar bone regeneration. Extending this design, an enzyme-responsive nanogel (TPP-SAT) composed of TPP, superoxide dismutase (SOD) and catalase (CAT) was developed, which targeted mitochondria, converted ROS into O₂ and relieved hypoxia, thereby rebalancing M1/M2 macrophages and inhibiting alveolar bone resorption (Figure 3d)^[100].

Carbon dots (CDs) can scavenge ROS, activate multiple endogenous protective pathways and regulate mitophagy, thereby collectively preserving mitochondrial homeostasis and ameliorating periodontal tissue destruction. For example, fisetin (FIS)-derived carbon dots (FIS-CDs) reduced intracellular ROS and activated mitophagy by downregulating the SUMOylation of sirtuin 3 (SIRT3) SUMOylation, thereby attenuating periodontal inflammation, inhibiting alveolar bone loss, and promoting periodontal tissue regeneration (Figure 3c)^[101]. Similarly, melatonin-derived carbon dots (MT-CDs) effectively scavenged intracellular ROS, maintained mitochondrial homeostasis and suppressed inflammatory cytokine production via the nuclear factor erythroid 2-related factor (Nrf2)/heme oxygenase-1 (HO-1) pathway^[102].

Functional hydrogels serve as reservoirs for sustained release of therapeutic agents, thereby reshaping the periodontal microenvironment. Antibacterial hydrogels are designed to eliminate bacteria in periodontal pockets, thereby alleviating the inflammatory cascades. A photocrosslinked hydrogel loaded with antimicrobial peptide AH-12 inhibited key pathogens (Fusobacterium nucleatum, P. gingivalis, and Streptococcus gordonii), stabilized mitochondrial Ca²⁺ levels, reduced mtROS production and mtDNA release, thereby alleviating inflammation and promoting tissue repair^[22]. Immunomodulatory hydrogels are intended to regulate the immune microenvironment to promote periodontal tissue regeneration. A hybrid hydrogel (AA@GO), composed of sodium alginate (SA), carboxymethyl chitosan (CCS), and graphene oxide (GO), promoted mitophagy, eliminated excess ROS, and improved mitochondrial function in macrophages via asiatic acid (AA) delivery, thereby exerting anti-inflammatory effects and enhancing tissue repair (Figure 4)^[103]. Notably, functional hydrogels serve as drug delivery systems to exert therapeutic effects while influencing cellular behavior via their three-dimensional (3D) network and mechanical microenvironment.

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Figure 4. (a) Schematic diagram of AA@GO hydrogel for diabetic periodontitis via mitophagy-mediated M2 macrophage polarization; (b) Schematic diagram of AA@GO hydrogel synthesis; (c) Status comparison before and after AA@GO hydrogel gelatinization; (d) SEM images of AA@GO hydrogel; (e,f) Expression analysis of PINK1 and BNIP3 by qRT-PCR in RAW264.7 cells across groups; (g) TEM images indicated differences in mitophagy between groups; (h) Colocalization immunofluorescence images of the expression of LC3 and TOM₂O in RAW264.7 cells. Reproduced from reference^[103]. CC BY 4.0. SEM: scanning electron microscopy; TEM: transmission electron microscopy; AA@GO: hybrid hydrogel; PINK1: PTEN-induced kinase 1; BNIP3: BCL2 and adenovirus E1B 19 kDa-interacting protein 3; ROS: reactive oxygen species; CCS: carboxymethyl chitosan; SA: sodium alginate; GO: graphene oxide; Gel: ROS-responsive hydrogel; HL: high glucose+LPS; mtRNA: mitochondrial RNA; LC3: microtubule-associated protein 1 light chain 3.

For severe periodontitis with obvious bone defects, improving the periodontal microenvironment alone is insufficient to achieve tissue regeneration. Therefore, scaffolds with the capacity to guide cell migration and differentiation are indispensable. For example, 3D-printed molybdenum-containing bioactive glass ceramic (Mo-BGC) scaffolds induced M2 polarization by reprogramming macrophage metabolism from glycolysis to OXPHOS in vitro and orchestrated the regeneration of bone, periodontal ligament, and cementum in a canine critical-size periodontal defect model^[104].

In summary, anti-inflammatory and immunomodulatory mitochondria-regulating biomaterials restore mitochondrial homeostasis to reprogram macrophage polarization and inhibit inflammatory signaling, thereby preventing periodontal tissue destruction while promoting regeneration. Future research should prioritize multi-target platforms that integrate complementary mechanisms.

4.2 Osteogenic mitochondria-regulating biomaterials

Progressive alveolar bone resorption is a core pathological feature of periodontitis and the primary cause of tooth loosening and tooth loss^[105]. Under physiological conditions, mitochondria maintain bone homeostasis by regulating the balance between osteoblasts and osteoclasts, as well as the function of BMSCs^[106]. However, in periodontitis, mitochondrial dysfunction suppresses bone formation while promoting bone resorption. Therefore, mitochondria-regulating biomaterials capable of restoring mitochondrial homeostasis to promote periodontal bone regeneration are of great importance and imperative. Herein, the representative biomaterials are summarized and shown in Table 2.

Naturally derived small-molecule polyphenols scavenge mtROS and protect mitochondria, thereby alleviating inflammatory bone resorption and promoting bone regeneration. Resveratrol (RSV), a grape-derived polyphenol^[107], suffers from low stability, poor aqueous solubility, limited bioavailability, and rapid metabolism. To overcome these limitations, RSV was crosslinked with guanidine-grafted ethylene glycol chitosan (GGC) via zinc ion (Zn²⁺)-based metal coordination bonds to construct a mitochondria-targeted nanocarrier system (GGC-Zn²⁺-RSV). GGC-Zn²⁺-RSV escaped lysosomal entrapment, alleviated mitochondrial dysfunction, and restored the osteogenic differentiation capacity of PDLSCs, ultimately repairing damaged periodontal tissue^[108]. Rather than active targeting, another study encapsulated RSV in gold nanocages embedded in a near-infrared (NIR) light-responsive hydrogel (RSV-Au@H) to achieve on-demand RSV release, which effectively ameliorated oxidative stress, repaired mitochondrial dysfunction, and improved osteoblast mitochondrial morphology, thereby shortening the cementum–enamel junction-alveolar bone crest distance of the first molar by approximately 55% on the buccal side and 36% on the palatal side, and increasing BV/TV by approximately 48% after 4 weeks of treatment^[30].

Synthetic polymeric vesicles scavenge ROS via surface chemical modification while releasing encapsulated therapeutic agents from their cores to activate mitophagy, preserving osteoblast function and promoting bone formation. Polymersomes, a typical subset of synthetic polymeric vesicles, exhibit this dual function. Specifically, a ginsenoside Rd (Rd)-loaded antioxidative polymersome (RdAP) was developed with a ROS-scavenging shell and a Rd-releasing core to activate mitophagy^[109]. In a mouse periodontitis model, RdAP reduced oxidative DNA damage, increased mitophagic flux 2.5-fold, and maintained mitochondrial homeostasis, thereby increasing the bone mass by 1.37-fold.

Inorganic metal-based nanozymes scavenge ROS and generate O₂ by mimicking SOD and CAT activities, thereby restoring mitochondrial homeostasis and promoting the osteogenic differentiation of PDLSCs. Manganese dioxide (MnO₂) is a representative metal-based nanozyme with robust catalytic activity, but its clinical application is often constrained by aggregation and rapid clearance. Therefore, MnO₂ was incorporated into nanoscale mesoporous UiO-66 metal-organic frameworks (MOFs) to construct a cascade catalytic system (MnO₂@UiO-66), which enhanced mitophagy via the SIRT1-FOXO3-BNIP3 signaling axis and restored mitochondrial homeostasis, ultimately alleviating inflammatory bone resorption^[110].

MOFs combine their intrinsic redox activity for scavenging ROS with porous architectures for therapeutic molecule loading, activating osteogenic signaling pathways to promote alveolar bone regeneration. Among them, zirconium (Zr)-based mesoporous MOF nanoparticles HMUiO-66-NH₂ scavenged ROS and enhanced the osteogenic differentiation of BMSCs via the Wnt and TGF-β signaling pathways, thereby facilitating bone repair^[111].

In conclusion, mitochondria-regulating biomaterials preserve osteoblast function, suppress osteoclast activity, and promote alveolar bone regeneration, demonstrating significant potential for periodontal bone repair. Unlike traditional bone graft materials, mitochondria-regulating biomaterials restore bone metabolic imbalance by targeting mitochondria, offering well-defined mechanisms and sustained therapeutic effects.

4.3 Multifunctional mitochondria-regulating biomaterials

The pathogenesis of periodontitis involves multiple factors, including bacterial infection, immune dysfunction, and abnormal bone metabolism, which collectively contribute to periodontal tissue destruction^[12]. Therefore, targeting a single factor is often insufficient to achieve satisfactory tissue repair. Since mitochondria regulate inflammation and bone metabolism, modulating mitochondrial function may simultaneously mitigate inflammation and enhance bone regeneration, positioning mitochondria as promising therapeutic targets. Accordingly, biomaterials that modulate mitochondrial function hold great potential for periodontitis treatment and can be categorized into biomimetic systems, hybrid composite systems, nanozyme catalytic systems, and smart responsive systems (Table 3).

Biomimetic systems utilize natural structures including lipid droplets and EVs to enable precise mitochondria-targeted delivery and multifunctional integration. A biomimetic lipid droplet system (GA@LDs-CRAMP) was constructed by anchoring cathelicidin-related antimicrobial peptide (CRAMP) onto macrophage-derived LDs and encapsulating gambogic acid (GA) within the hydrophobic core. By targeting mitochondria, this system inhibited periodontal pathogens, reduced oxidative stress in gingival fibroblasts, and induced M2 macrophage polarization via the Nrf2 and nuclear factor-kappa B (NF-κB) pathways, thereby attenuating inflammation and alveolar bone loss (Figure 5a)^[112]. In parallel, EVs have also been explored as biomimetic carriers. Lactobacillus reuteri-derived EVs loaded with ultra-small cerium oxide (CeO₂) nanoparticles and hyaluronic acid (HA)-modified single-atom cerium nanozymes (Ce-N-C@HA) were combined to construct a dual-module cerium nanosystem, which effectively scavenged ROS and induced M2 macrophage polarization, thereby alleviating the inflammatory microenvironment^[113]. Collectively, these biomimetic systems leverage natural carriers to deliver therapeutic agents specifically to mitochondria, achieving targeted intervention with minimal off-target effects.

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Figure 5. (a) Schematic diagram of GA@LDs-CRAMP preparation and promotion of periodontal tissue restoration. Reproduced from reference^[112]. CC BY 4.0; (b) Schematic illustration of the construction and mechanism of Ce-N-C@HA and CeO₂-EV for periodontitis recovery. Reproduced from reference^[113]. CC BY 4.0; (c) Schematic diagram of GM/OHA-GZN&M hydrogel for periodontitis repair. Reproduced from reference^[116]. CC BY 4.0; (d) Schematic illustration of the SFD/CS/ZIF-8@QCT hydrogel for regenerating alveolar bone in periodontitis. Reproduced from reference^[117]. CC BY 4.0. LPS: lipopolysaccharide; OXPHOS: oxidative phosphorylation; TNF-α: tumor necrosis factor-α; IL-1β: interleukin-1β; mTOR: mammalian target of rapamycin; PDLSCs: periodontal ligament stem cells; NF-κB: nuclear factor-kappa B; SOD: superoxide dismutase; CAT: catalase; ATP: adenosine triphosphate; SFD/CS/ZIF-8@QCT: injectable composite hydrogel; ROS: reactive oxygen species; HA: hyaluronic acid; ZIF-8: zeolitic imidazolate framework-8; NLRP3: NOD-like receptor family pyrin domain containing 3; OCN: osteocalcin; INF-γ: interferon-γ; GZN: grape seed extract-zinc coordination nanoparticle; MCP-1: monocyte chemoattractant protein 1; MMP: mitochondrial membrane potential.

Hybrid composite systems integrate multiple functional components into a single platform via physical or chemical interactions to achieve combined antibacterial, anti-inflammatory, and osteogenic effects. Among diverse functional components, polyphenols represent a major class due to their intrinsic ability to bind mitochondrial outer membrane proteins and scavenge mtROS, making them attractive candidates for mitochondrial regulation^[114]. Grape seed extract (GSE), a polyphenol-rich natural compound^[115], was incorporated with GSE-Zn coordination nanoparticles and melittin into a mitochondria-targeting hydrogel (GM/OHA-GZN&M hydrogel) prepared by crosslinking modified gelatin (GelMA) and oxidized hyaluronic acid (OHA). The hydrogel eliminated bacteria and restored mitochondrial function by scavenging mtROS, thereby promoting M2 macrophage polarization and osteogenesis, ultimately leading to alveolar bone regeneration (Figure 5c)^[116]. To further explore the therapeutic potential of polyphenols, an injectable composite hydrogel (SFD/CS/ZIF-8@QCT) was developed to co-deliver quercetin and zinc ions via pH-responsive zeolitic imidazolate framework-8 (ZIF-8). SFD/CS/ZIF-8@QCT eliminated P. gingivalis, restored energy metabolism, mitigated oxidative stress, and reversed excessive mitophagy via the PI3K/Akt signaling pathway, reprogrammed macrophages toward M2 polarization, enhanced osteogenesis and angiogenesis, and eventually facilitated periodontal alveolar bone regeneration (Figure 5d)^[117]. Additionally, a polyphenol derivative, caffeic acid phenethyl ester (CAPE), was encapsulated within ZIF-8, which was incorporated into a phenylboronic acid (PBA)-modified carboxymethyl chitosan (CC) hydrogel (ACP@Z@C) for controlled release. The ACP@Z@C hydrogel exhibited antibacterial activity, scavenged ROS, alleviated inflammation, and restored mesenchymal stem cell (MSC) mitochondrial function by activating the SIRT1/p-AMPK/PGC-1α pathway, thereby promoting MSC osteogenic differentiation and alveolar bone regeneration (Figure 7a)^[118]. Metal-polyphenol coordination further enhances the functionality of polyphenols by combining their ROS-scavenging capacity with the catalytic activity of metal ions. Tannic acid coordinates with Mn and Zn to form Mn-Zn-tannic acid@SS31 (MZT@S) nanozymes, which were loaded into a PLGA-PEG-PLGA (PPP) thermosensitive hydrogel (MZT@S/PPP). This system enhanced mitochondrial localization, promoted mtROS clearance, and restored OXPHOS, thereby promoting osteogenesis, angiogenesis, and M2 polarization, ultimately inhibiting bone resorption and stimulating bone formation in diabetic periodontitis (Figure 6)^[119]. Overall, hybrid composite systems achieve multifunctionality via rational combination of diverse active components, offering a flexible and versatile platform for periodontitis therapy.

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Figure 7. (a) Schematic diagram of ACP@Z@C hydrogel scavenging ROS to promote MSC osteogenesis and periodontal tissue regeneration. Reproduced from reference^[118]. CC BY 4.0; (b) Schematic diagram of the synthesis process and therapeutic mechanism of J-CeM@Au for periodontitis treatment. Reproduced from reference^[125]. CC BY 4.0; (c) Schematic diagram of material design of Au@CeO₂-DMF and its triple-combination therapy for periodontitis through antioxidant effect, mitochondrial maintenance, and immunomodulatory mechanisms. Reproduced from reference^[122]. CC BY 4.0. MSC: mesenchymal stem cell; ROS: reactive oxygen species; DMF: dimethyl fumarate; NLRP3: NOD-like receptor family pyrin domain containing 3; mtROS: mitochondrial reactive oxygen species; PDLCs: periodontal ligament cells; MMP: matrix metalloproteinase; TNF-α: tumor necrosis factor-α; IL-1β: interleukin-1β; NIR: near-infrared; ZIF-8: zeolitic imidazolate framework-8; SIRT1: SUMOylation of sirtuin 1; CAPE: caffeic acid phenethyl ester; ATP: adenosine triphosphate; PBA: phenylboronic acid; TFAM: mitochondrial transcription factor A; PGC-1α: peroxisome profiferator-activated receptor-γ coactivator 1α; MSN: mesoporous silica nanoparticle.

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Figure 6. (a) Schematic illustration of MZT@S/PPP hydrogel preparation and its multifunctional effects during the progression of diabetes-associated periodontitis; (b) Schematic illustration of the synthesis of MZT@S; (c) Schematic illustration of the MZT@S/PPP hydrogel; (d) SEM image of MZT@S; (e) TEM images of MZT and MZT@S; (f) SEM image of MZT@S/PPP; (g) Mitochondrial localization of FITC-labeled MZT@S and MZT in BMSCs after 3 h incubation. Mitochondria were stained with MitoTracker Red; (h) Representative intracellular ROS staining; (i) JC-1 staining images showing mitochondrial membrane potential; (j) MitoSOX staining for mtROS levels. Reproduced from reference^[119]. CC BY 4.0. PPP: PLGA-PEG-PLGA; MZT@S: Mn-Zn-tannic acid@SS31; SEM: scanning electron microscopy; TEM: transmission electron microscopy; ROS: reactive oxygen species; CAT: catalase; FITC: fluorescein isothiocyanate.

Nanozyme catalytic systems utilize metal nanoparticles to mimic natural antioxidant enzyme activities, thereby scavenging ROS, restoring mitochondrial function, alleviating periodontal inflammation, and preventing alveolar bone resorption. MnO₂ nanoparticles, mimicking SOD and CAT^[120], were encapsulated in hypoxia-educated PDLSC membranes (hPM) (MnO₂@hPM) to scavenge ROS, reverse metabolic disorders, alleviate mitochondrial dysfunction and restore the osteogenic potential of PDLSCs under inflammatory conditions^[121]. Similarly, a multifunctional yolk-shell nanozyme, Au@CeO₂-dimethyl fumarate (DMF), ameliorated mitochondrial dysfunction and immune dysregulation and eliminated endogenous ROS in vitro and effectively reestablished local periodontal homeostasis and alleviated ROS-induced tissue damage in a rat periodontitis model (Figure 7c)^[122]. These nanozymes operate through single or dual catalytic activities for ROS scavenging, whereas nanozyme cascade systems integrate multiple enzymatic reactions to simultaneously intervene at multiple nodes of mitochondrial oxidative stress, such as consuming upstream substrates and converting intermediate H₂O₂. For example, a cascade catalytic nanoplatform based on glucose oxidase (GOx) and CAT can consume excessive local glucose while simultaneously converting the generated H₂O₂ into O₂^[123]. Such cascade systems can cut off high-glucose-induced mitochondrial oxidative stress at its source and achieve deeper metabolic reprogramming, thereby breaking the self-amplifying cycle of ROS, inflammation, and hypoxia.

Smart responsive systems exploit the sensitivity of materials to microenvironmental stimuli to achieve spatiotemporally controllable drug release, enabling anti-inflammatory and pro-regenerative effects. In response to the acid microenvironment in periodontitis, pH-responsive mitochondria-targeted nanocarriers (PPTB NPs) loaded with calcium chelator BAPTA-AM were designed to release drugs under acidic conditions to chelate Ca²⁺ around and inside mitochondria, inhibit mPTPs opening, and suppress pro-inflammatory macrophage polarization^[124]. In addition, a NIR light-responsive Janus nanomotor (J-CeM@Au) was developed by coating cerium dioxide-doped mesoporous silica (CeM) with gold nanoparticles (AuNP), which effectively eliminated periodontal pathogens, scavenged excessive ROS, and induced M1-to-M2 macrophage polarization via the NF-κB pathway, thereby alleviating local inflammation and promoting periodontal regeneration (Figure 7b)^[125]. Both systems rely on a single stimulus, which may clear ROS too early and weaken the antibacterial ability, whereas periodontitis progresses through sequential phases of infection, oxidative stress, and inflammation. Therefore, sequential drug release is required, and one promising approach is to design nanoplatforms that respond to multiple triggers and spatiotemporally release each agent.

In conclusion, multifunctional mitochondria-targeting biomaterials integrate mitochondrial restoration with antibacterial, anti-inflammatory, and osteogenic functions, demonstrating significant potential for periodontitis therapy. Various platforms have been explored, including biomimetic systems, hybrid composite systems, nanozyme catalytic systems, and intelligent responsive systems, providing valuable design insights. Future efforts should further simplify material design, enhance biosafety, and establish comprehensive preclinical evaluation systems.

5. Challenges and Future Perspectives

Mitochondria-regulating biomaterials have shown encouraging therapeutic efficacy in preclinical models, with current materials achieving mitochondrial targeting via TPP, SS31, PDLSC membrane-mediated homologous targeting, and polyphenol-mediated mechanisms, enabling stimulus-responsive release under ROS, NIR, or pH conditions, and integrating antibacterial, anti-inflammatory, immunomodulatory, and osteogenic functions into a single platform. However, most evidence is derived from rodent models and in vitro assays, with limited evaluation of targeting specificity, long-term safety, and the evaluation of periodontal retention and degradation (Table 4), which hinders clinical translation.

Therefore, several challenges still need to be addressed. First, the in vivo fate of mitochondrial-regulating materials remains unclear, as their retention in the periodontal pocket, cellular uptake, and mitochondrial targeting efficiency are rarely verified. Second, the pathological process of periodontitis is dynamic, and current biomaterials cannot precisely release therapeutic agents in appropriate amounts in response to disease progression. Third, the widely used animal models fail to recapitulate key features of human chronic periodontitis such as microbial ecological dysbiosis, immune memory, and tissue remodeling, rendering efficacy data unreliable for predicting long-term regenerative outcomes in complex clinical settings. Finally, the long-term safety of heavy-metal-based inorganic nanozymes and frameworks (e.g., Ce, Mn, Zr, Au) remains unclear, as degraded metal ions may accumulate in periodontal tissues or enter the bloodstream and deposit in organs such as the liver and spleen, and may interfere with autophagy-lysosomal pathways and disturb the mitophagy baseline in normal cells.

To address these challenges, several strategies can be adopted. First, fluorescent or radioactive labeling combined with live imaging, flow cytometry, and super-resolution microscopy can track material retention, cellular uptake, and mitochondrial targeting in real time. Second, multi-layered and multifunctional delivery systems, and three-dimensional scaffolds should be constructed to achieve the programmed release and spatiotemporal synergy of anti-inflammatory cytokines, osteogenic bioactive molecules, and therapeutic agents. Third, humanized mouse models and oral microbiome transplantation can better recapitulate human periodontal pathology and immune responses, while single-cell genomics can identify conserved and divergent features between animal models and human disease. Finally, for safety concerns such as metal ion accumulation and autophagy interference, systematic toxicological evaluation in large animal models is required.

In summary, mitochondria-regulating biomaterials stand at a pivotal juncture in periodontitis therapy, transitioning from proof-of-concept approaches toward functional repair strategies. The deep integration of materials science and biomedicine holds promise for addressing current bottlenecks, propelling the field toward a new developmental stage.

Authors contribution

Yan X: Investigation, writing-original draft.

Hu X: Conceptualization.

Wei J: Conceptualization, writing-review & editing.

Conflicts of interest

Junchao Wei is a Youth Editorial Board Member of BME Horizon. The other authors declare no conflicts of interest.

Ethical approval

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Consent for publication

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Availability of data and materials

Not applicable.

Funding

This work was supported by the financial support from the National Natural Science Foundation of China (Grant No. 52463017), Natural Science Foundation of Jiangxi Province (Grant No. 20242BAB26161).

Copyright

© The Author(s) 2026.