Microenvironment-responsive nanomotors enable enhanced biofilm penetration and immune reprogramming for peri-implantitis therapy.

Microenvironment-responsive nanomotors enable enhanced biofilm penetration and immune reprogramming for peri-implantitis therapy - PMC Skip to main content An official website of the United States government Here's how you know Here's how you know Official websites use .gov A .gov website belongs to an official government organization in the United States. Secure .gov websites use HTTPS A lock ( Lock Locked padlock icon ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites. Search Log in Dashboard Publications Account settings Log out Search… Search NCBI Primary site navigation Search Logged in as: Dashboard Publications Account settings Log in Search PMC Full-Text Archive Search in PMC Journal List User Guide PERMALINK Copy As a library, NLM provides access to scientific literature. 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Learn more: PMC Disclaimer | PMC Copyright Notice J Nanobiotechnology . 2026 Mar 7;24:355. doi: 10.1186/s12951-026-04244-1 Search in PMC Search in PubMed View in NLM Catalog Add to search Microenvironment-responsive nanomotors enable enhanced biofilm penetration and immune reprogramming for peri-implantitis therapy Wanmeng Wang Wanmeng Wang 1 School and Hospital of Stomatology and Institute of Stomatology, Tianjin Key Laboratory of Oral Soft and Hard Tissues Restoration and Regeneration, Tianjin Medical University, No. 12 Qixiangtai Road, Heping District, Tianjin, 300070 China 2 State Key Laboratory Cultivation Base for Oral Disease Research, Prevention and Treatment, and Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing, 210029 China Find articles by Wanmeng Wang 1, 2, # , Jiahao Yun Jiahao Yun 1 School and Hospital of Stomatology and Institute of Stomatology, Tianjin Key Laboratory of Oral Soft and Hard Tissues Restoration and Regeneration, Tianjin Medical University, No. 12 Qixiangtai Road, Heping District, Tianjin, 300070 China Find articles by Jiahao Yun 1, # , Lipeng Niu Lipeng Niu 1 School and Hospital of Stomatology and Institute of Stomatology, Tianjin Key Laboratory of Oral Soft and Hard Tissues Restoration and Regeneration, Tianjin Medical University, No. 12 Qixiangtai Road, Heping District, Tianjin, 300070 China Find articles by Lipeng Niu 1 , Yunkai Liang Yunkai Liang 1 School and Hospital of Stomatology and Institute of Stomatology, Tianjin Key Laboratory of Oral Soft and Hard Tissues Restoration and Regeneration, Tianjin Medical University, No. 12 Qixiangtai Road, Heping District, Tianjin, 300070 China Find articles by Yunkai Liang 1 , Yuan Tian Yuan Tian 1 School and Hospital of Stomatology and Institute of Stomatology, Tianjin Key Laboratory of Oral Soft and Hard Tissues Restoration and Regeneration, Tianjin Medical University, No. 12 Qixiangtai Road, Heping District, Tianjin, 300070 China Find articles by Yuan Tian 1 , Ning Wang Ning Wang 1 School and Hospital of Stomatology and Institute of Stomatology, Tianjin Key Laboratory of Oral Soft and Hard Tissues Restoration and Regeneration, Tianjin Medical University, No. 12 Qixiangtai Road, Heping District, Tianjin, 300070 China Find articles by Ning Wang 1 , Yunjia Song Yunjia Song 1 School and Hospital of Stomatology and Institute of Stomatology, Tianjin Key Laboratory of Oral Soft and Hard Tissues Restoration and Regeneration, Tianjin Medical University, No. 12 Qixiangtai Road, Heping District, Tianjin, 300070 China Find articles by Yunjia Song 1 , Bo Chen Bo Chen 1 School and Hospital of Stomatology and Institute of Stomatology, Tianjin Key Laboratory of Oral Soft and Hard Tissues Restoration and Regeneration, Tianjin Medical University, No. 12 Qixiangtai Road, Heping District, Tianjin, 300070 China Find articles by Bo Chen 1, ✉ , Hong Bai Hong Bai 3 Key Laboratory of Immune Microenvironment and Disease of the Ministry of Education, Department of Immunology, Tianjin Institute of Immunology, Tianjin Medical University, Tianjin, 300070 China Find articles by Hong Bai 3, ✉ , Ying Li Ying Li 1 School and Hospital of Stomatology and Institute of Stomatology, Tianjin Key Laboratory of Oral Soft and Hard Tissues Restoration and Regeneration, Tianjin Medical University, No. 12 Qixiangtai Road, Heping District, Tianjin, 300070 China Find articles by Ying Li 1, ✉ Author information Article notes Copyright and License information 1 School and Hospital of Stomatology and Institute of Stomatology, Tianjin Key Laboratory of Oral Soft and Hard Tissues Restoration and Regeneration, Tianjin Medical University, No. 12 Qixiangtai Road, Heping District, Tianjin, 300070 China 2 State Key Laboratory Cultivation Base for Oral Disease Research, Prevention and Treatment, and Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing, 210029 China 3 Key Laboratory of Immune Microenvironment and Disease of the Ministry of Education, Department of Immunology, Tianjin Institute of Immunology, Tianjin Medical University, Tianjin, 300070 China ✉ Corresponding author. # Contributed equally. Received 2026 Jan 4; Accepted 2026 Feb 24; Collection date 2026. © The Author(s) 2026 Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/ . PMC Copyright notice PMCID: PMC13081636  PMID: 41794707 Abstract Background Peri-implantitis is driven by persistent multispecies biofilms and a pathological inflammatory microenvironment characterized by elevated reactive oxygen species (ROS), acidic pH, and sustained pro-inflammatory macrophage activation. These coupled features severely limit the efficacy of conventional antimicrobial therapies by restricting drug penetration into mature biofilms and perpetuating immune dysregulation. Therapeutic strategies capable of simultaneously overcoming biofilm mass-transport barriers and restoring immune homeostasis remain lacking. Results Herein, we report a microenvironment-responsive nanomotor system (M-CaO₂-CL) that converts pathological inflammatory cues into sustained autonomous motion, enabling active biofilm penetration and concurrent immunomodulation. Triggered by elevated hydrogen peroxide (H₂O₂) and sustained by acidic pH, the nanomotors generate continuous oxygen-driven propulsion, facilitating deep infiltration into dense biofilm matrices and overcoming diffusion-limited transport. This motion-enabled behavior markedly enhances antibacterial efficacy, particularly when combined with mild photothermal treatment under near-infrared irradiation (< 48 °C), achieving efficient biofilm disruption without detectable collateral tissue damage. Beyond antibiofilm activity, the nanomotor platform exhibits intrinsic antioxidant and anti-inflammatory functions, effectively scavenging excessive ROS and reprogramming macrophages from a pro-inflammatory M1 phenotype toward a reparative M2 phenotype. In a rat peri-implantitis model, M-CaO₂-CL treatment significantly reduced bacterial burden, suppressed pro-inflammatory cytokine expression, and preserved peri-implant bone architecture. Conclusions Collectively, this study demonstrates a multifunctional nanomotor-based therapeutic strategy that integrates inflammation-responsive propulsion, enhanced biofilm penetration, mild photothermal disinfection, and immune reprogramming. By harnessing pathological microenvironmental cues as endogenous driving forces, the M-CaO₂-CL nanomotor effectively addresses key biological barriers in peri-implantitis, establishing a promising nanotherapeutic platform for biofilm-associated inflammatory diseases. Graphical abstract Supplementary Information The online version contains supplementary material available at 10.1186/s12951-026-04244-1. Keywords: Peri-implantitis, Microenvironment-responsive nanomotors, Biofilm penetration, Mild photothermal disinfection, Immunomodulation Introduction Dental implant restoration has become a primary rehabilitation method for both partial and complete edentulism, driven by its favorable long-term success rates and functional outcomes. Correspondingly, the global dental implant market is projected to reach approximately $9.5 billion by 2032, with an estimated annual growth rate of 6.5% [ 1 – 3 ]. However, the rapid expansion of implant placement has been accompanied by a steadily increasing burden of peri-implant diseases, which have emerged as a major challenge in contemporary implant dentistry. Among these conditions, peri-implantitis is recognized as a destructive, biofilm-driven inflammatory disease rather than a simple biological complication. If left untreated, peri-implantitis leads to progressive peri-implant bone resorption, loss of osseointegration, and ultimately implant failure [ 3 – 5 ]. Recent systematic analyses report a weighted prevalence of peri-implantitis of approximately 22% after 20 years of implant function, underscoring its substantial long-term clinical impact and the urgent need for more effective therapeutic strategies [ 6 ]. The persistence and pathogenicity of peri-implantitis are largely attributable to the formation of mature multispecies biofilms on implant surfaces. These biofilms exhibit complex three-dimensional architectures enriched with dense extracellular polymeric substances (EPS), which create formidable physical and biochemical barriers to antimicrobial penetration [ 7 – 10 ]. In addition, limited oxygen diffusivity within biofilms results in a hypoxic microenvironment, underscoring the limitations of oxygen-dependent therapies and the need for alternative or complementary antibacterial strategies capable of functioning effectively under hypoxic biofilm conditions. Current clinical management relies on nonsurgical or surgical interventions, with nonsurgical therapy serving as the indispensable first-line treatment. Mechanical debridement, often supplemented with adjunctive antimicrobials, remains the standard modality for disrupting biofilms and reducing microbial load [ 5 , 11 ]. Nevertheless, mechanical debridement alone is frequently inadequate for dismantling structured biofilms adherent to implant surfaces [ 12 ]. Adjunctive antibiotics or antimicrobial rinses face well-recognized limitations, including the risk of antibiotic resistance, potential local cytotoxicity to host cells, and limited penetration into deeper layers of established biofilms [ 13 – 15 ]. In addition, current evidence does not support the routine use of systemic or local antibiotics as adjuncts to non-surgical or surgical peri-implantitis therapy [ 5 , 13 , 16 ]. In response to these limitations, alternative antimicrobial strategies such as photodynamic therapy (PDT) [ 17 , 18 ] and chemodynamic therapy (CDT) [ 19 ] have been explored. These approaches rely on the generation of reactive oxygen species (ROS) to induce bacterial killing through oxidative damage. However, their effectiveness is profoundly restricted by the intrinsic hypoxia of mature biofilms, which limits ROS generation and diminishes bactericidal efficacy. Moreover, excessive ROS production may exacerbate oxidative injury to surrounding peri-implant tissues, potentially aggravating inflammation and impairing healing. Consequently, despite considerable advances, the effective eradication of established peri-implant biofilms remains a major therapeutic challenge. Beyond microbial factors, increasing evidence indicates that the peri-implant inflammatory microenvironment plays a decisive role in disease progression. Peri-implantitis lesions are associated with elevated local oxidative stress/ROS burden [ 20 , 21 ], a reduced (acidic) pH in the peri-implant crevicular/biofilm milieu [ 22 ], and excessive activation of pro-inflammatory immune cells [ 23 , 24 ]. These pathological features not only promote microbial dysbiosis but also sustain a vicious cycle of inflammation and tissue destruction. In particular, pronounced infiltration of M1-polarized macrophages has been identified in peri-implant lesions [ 25 ], where they secrete high levels of pro-inflammatory cytokines and ROS, further amplifying inflammatory signaling and accelerating bone resorption [ 26 ]. Despite growing recognition of the central role of immune dysregulation in peri-implantitis, therapeutic strategies capable of simultaneously penetrating dense biofilms and restoring immune homeostasis remain largely unmet. Photothermal therapy (PTT) has recently attracted attention as a precise, non-antibiotic antibacterial strategy for biofilm eradication. Under near-infrared (NIR) irradiation, photothermal agents convert light energy into localized heat, leading to disruption of bacterial membranes, denaturation of proteins, and damage to nucleic acids. Our previous work demonstrated that a baicalein-loaded mesoporous Prussian blue nanoplatform exhibited potent photothermal, antioxidant, and anti-inflammatory effects in the treatment of periodontitis [ 27 ]. However, peri-implantitis typically progresses more rapidly and aggressively than periodontitis [ 28 ]. Eradication of its dense and mature biofilms often requires temperatures exceeding 60 °C, which may induce collateral damage to peri-implant tissues and exacerbate immune dysregulation [ 29 ]. These concerns have prompted increasing interest in mild-temperature PTT, which maintains hyperthermia below 48 °C. Although mild hyperthermia has shown promise in other biomedical contexts, including cancer therapy [ 30 ], its ability to sufficiently weaken mature peri-implant biofilms remains uncertain. Achieving effective mild PTT therefore requires photothermal materials with high photothermal conversion efficiency at relatively low temperatures. Mesoporous polydopamine (MPDA) has emerged as a promising candidate due to its strong NIR absorbance, excellent biocompatibility, and tunable mesoporous structure. In addition, our work and others have shown that combining photothermal and photodynamic mechanisms can reduce the temperature threshold required to achieve antibacterial efficacy in periodontitis models [ 31 , 32 ]. Nevertheless, the dense EPS matrix of mature peri-implant biofilms continues to limit heat diffusion and restrict therapeutic penetration. These challenges underscore the need for therapeutic platforms that not only support mild PTT but also actively enhance biofilm penetration and provide complementary bactericidal mechanisms beyond thermal effects alone. Recent advances in nanomotor technology offer a potential solution to these challenges. By converting environmental energy into autonomous motion, nanomotors can overcome diffusion limitations inherent to biological systems, thereby enhancing penetration into complex matrices, increasing contact with bacteria, and improving local therapeutic delivery [ 33 – 36 ]. While ROS-responsive nanomotors have demonstrated encouraging therapeutic benefits in tumor and renal disease models [ 36 , 37 ], their application in peri-implantitis remains largely unexplored. Importantly, the peri-implant inflammatory microenvironment is characterized by elevated ROS—particularly H₂O₂—and an acidic pH resulting from anaerobic bacterial metabolism [ 38 – 41 ]. These pathological hallmarks provide ideal endogenous cues for activating microenvironment-responsive nanomotors tailored to the peri-implantitis setting. In addition to effective biofilm eradication, successful peri-implantitis therapy must address chronic inflammation and immune imbalance. Lignin, a renewable natural polyphenol, has attracted increasing interest owing to its potent antioxidant and anti-inflammatory properties [ 42 , 43 ]. Lignin suppresses the production of pro-inflammatory cytokines such as IL-6 and TNF-α, inhibits NF-κB signaling, enhances the expression of antioxidant enzymes [ 44 ], and promotes immunoregulatory cytokines including IL-4 and IL-10 [ 45 ]. Moreover, lignin exhibits excellent biocompatibility, low toxicity, high photostability, and resistance to chemical and enzymatic degradation, making it well suited for biomedical applications [ 46 – 48 ]. These features position lignin as an attractive component for integration into nanotherapeutic platforms that aim to combine antibiofilm activity with immunomodulatory functions. Alongside MPDA and lignin, catalase (CAT) and calcium peroxide (CaO₂) function as microenvironment-responsive propulsion-enabling components. CAT catalyzes the decomposition of excessive H₂O₂ into oxygen, while CaO₂ undergoes acid-triggered decomposition to generate additional H₂O₂. However, single-function materials alone are insufficient to penetrate mature biofilms, alleviate oxidative stress, and modulate immune responses simultaneously. This limitation highlights the need for a multifunctional, microenvironment-responsive system capable of integrating these distinct yet complementary therapeutic actions. To address these challenges, we developed an inflammatory microenvironment–responsive nanomotor (M-CaO₂-CL) that integrates MPDA, CaO₂, CAT, and lignin into a single platform. This design leverages the specific ROS/acidic pH cues of the peri-implantitis microenvironment to fuel autonomous motion, which is expected to overcome biofilm barriers while concurrently delivering immunomodulatory cargo to disrupt the cycle of inflammation. This process suggests a microenvironment-triggered, two-step H₂O₂-to-O₂ propulsion mechanism rather than a single-step reaction [ 49 ]. This nanomotor is designed to achieve autonomous propulsion in response to pathological microenvironmental cues, enhance penetration into dense biofilms while enabling mild photothermal disinfection, and modulate immune responses through ROS scavenging and macrophage reprogramming. Through comprehensive in vitro investigations and validation in a rat peri-implantitis model, we evaluate the therapeutic potential of this multifunctional nanomotor for the treatment of biofilm-associated peri-implantitis. Materials and methods Materials Dopamine hydrochloride (DA), Pluronic F-127, 1,3,5-trimethylbenzene (TMB), ammonia solution (28–30%), paraffin wax, catalase (CAT), hydrogen peroxide solution, polyvinylpyrrolidone (PVP), and calcium chloride (CaCl₂) were purchased from Solarbio (Beijing, China). Lignin was obtained from Sigma-Aldrich (USA). All chemicals were used as received unless otherwise specified. Synthesis of MPDA Mesoporous polydopamine nanoparticles (MPDA NPs) were first synthesized following a previously reported protocol [ 50 ]. Briefly, a 50% (v/v) ethanol solution was prepared by mixing 100 mL ethanol with 100 mL of deionized water. Pluronic F-127 (2 g) and DA (1 g) were dissolved under stirring, followed by the addition of 4 mL TMB to form a stable emulsion. Ammonia solution (28–30%, 10 mL) was then added, and the mixture was stirred at 400 rpm for 10 h. The formed nanoparticles were collected by centrifugation (12,000 rpm, 20 min), washed with ethanol and water, and lyophilized to obtain MPDA NPs. Synthesis of M-CaO 2 Paraffin wax (0.5 g) was melted at 80 °C and mixed with 1 mL MPDA dispersion (20 mg/mL), followed by emulsification at 10,000 rpm for 1 min to form MPDA@Wax microspheres. Separately, PVP (0.3 g) and CaCl₂ (0.3 g) were dissolved in ethanol (15 mL) and mixed with MPDA@Wax (3 g). Subsequently, ammonia (0.8 M, 1 mL) and H₂O₂ (1 M, 200 µL) were added dropwise in an ice bath. After stirring for 15 min (300 rpm), the precipitate was collected, treated with chloroform to remove the wax core, washed with ethanol, and lyophilized to obtain CaO₂-coated MPDA (M-CaO₂). Synthesis of M-CaO 2 -CL M-CaO₂ (5 mL, 2 mg/mL) was mixed with CAT (10 µL; concentration as received) and lignin (500 µL, 5 mg/mL) under gentle stirring for 5 h. The product was collected via centrifugation (12,000 rpm, 20 min), washed with deionized water, and lyophilized. Supernatants were saved for loading efficiency analysis. Characterization Nitrogen adsorption–desorption isotherms were measured using the BET and NLDFT/GCMC methods. Morphologies were examined by SEM (Gemini 300, Zeiss, Germany) and TEM (Hitachi, Japan). Elemental distribution was assessed by energy-dispersive X-ray spectroscopy (EDX) mapping. The Janus-like architecture of M-CaO₂-CL nanomotors was further characterized by high-angle annular dark-field scanning transmission electron microscopy (HAADF-STEM, JSM-7800 F, JEOL, Japan). Hydrodynamic diameter, polydispersity index (PDI), and zeta potential were measured using a laser particle size analyzer (Malvern, UK). UV–vis spectra were recorded using a spectrophotometer (Shimadzu, Japan). FT-IR spectra were obtained using an FT-IR spectrometer (Thermo Fisher Scientific, USA). CAT loading was quantified using a Bradford protein assay, and lignin loading was determined from UV–vis calibration curves. Photothermal performance evaluation Photothermal behavior was assessed under 808 nm laser irradiation (0.5, 1.0, or 1.5 W/cm² for 10 min; Changchun Laser Technology Co., Ltd., China). M-CaO₂-CL suspensions (100 µg/mL in PBS) were irradiated at 0.5, 1.0, or 1.5 W/cm² for 10 min. Temperature changes were recorded every minute using an infrared thermal imager (Hikvision, China). The effects of M-CaO₂-CL NP concentration (50, 100, 200 µg/mL) and composition (MPDA, M-CaO₂, M-CaO₂-CL) on photothermal heating were also evaluated under 808 nm NIR irradiation (1.0 W/cm², 10 min). Photothermal stability of M-CaO₂-CL was assessed over repeated heating–cooling cycles. The photothermal conversion efficiency (η) was calculated according to standard methods using the following equations: Here, T max and T max, PBS represent the equilibrium maximum temperatures of the M-CaO₂-CL suspension and PBS, respectively, after 10 min of irradiation. T amb denotes the ambient temperature (25.0 °C). I and A refer to the laser power (1.0 W/cm²) and the absorbance of M-CaO₂-CL at 808 nm, respectively. m d and C d represent the mass of the solution (0.1 g) and the heat capacity of PBS (4.2 J/g·K), respectively. The heat transfer time constant ( τs ) was obtained from the linear fitting of the cooling profile. Motion performance, dissolved oxygen generation, and lignin release MPDA, M-CaO₂, and M-CaO₂-CL nanoparticles (NPs) were dispersed in PBS to obtain 1 mg/mL suspensions. To evaluate their motion behavior under combined stimuli, the NPs were exposed to 100 µM H₂O₂ + pH 6.0 with NIR irradiation (808 nm, 1.0 W/cm², 10 min). Briefly, 10 µL of NP suspension was added to 200 µL of the prepared H₂O₂-containing acidic PBS solution in a confocal dish, followed by placement of a coverslip to minimize liquid drift during observation. Real-time particle motion was recorded for 10 s using an inverted optical microscope (Olympus, Japan) equipped with a CMOS camera (Olympus DP28). The recorded videos were saved in AVI format for subsequent trajectory analysis. Motion videos were recorded following the same procedure described above for nanoparticle tracking analysis. Nanoparticle trajectories were extracted using ImageJ software, and mean square displacement (MSD) was calculated based on the standard two-dimensional displacement definition: The average velocity of nanomotors was further calculated from trajectory data to quantitatively compare propulsion efficiency under different conditions. To assess the microenvironment-dependent motility of M-CaO₂-CL nanomotors, 10 µL of NP suspension was added to 200 µL of the following substrate solutions: (i) PBS (pH 7.4), (ii) PBS (pH 6.0), (iii) PBS (pH 7.4) containing 100 µM H₂O₂, (iv) PBS (pH 6.0) containing 100 µM H₂O₂, (v) PBS (pH 6.0) containing 100 µM H₂O₂ under NIR irradiation (808 nm, 1.0 W/cm², 10 min). For inactive catalase (CAT) control experiments, M-CaO₂-CL nanomotors were prepared using thermally inactivated CAT (80 °C for 10 min) prior to motion analysis, and the same experimental procedures were followed. Ca²⁺ release from M-CaO₂-CL nanomotors was quantified under inflammation-mimicking conditions to evaluate CaO₂ decomposition behavior. Nanomotor suspensions (100 µg/mL) were incubated in PBS (pH 7.4) or PBS containing 100 µM H₂O₂ at pH 6.0 under NIR irradiation (808 nm, 1.0 W/cm²). At designated time points, samples were centrifuged and Ca²⁺ concentrations in the supernatant were measured using a commercial calcium assay kit. Photothermal heating behavior was first evaluated by monitoring temperature elevation of M-CaO₂-CL nanomotor suspensions (100 µg/mL) under continuous 808 nm NIR irradiation (1.0 W/cm²) in PBS at pH 7.4 or acidic H₂O₂-containing buffer (pH 6.0). Photothermal stability was subsequently assessed to determine whether structural evolution affects photothermal responsiveness. Nanomotor suspensions were subjected to repeated NIR irradiation on/off cycles (808 nm, 1.0 W/cm², 10 min per cycle) with natural cooling between cycles, and temperature changes were recorded using an infrared thermal imager. The dissolved oxygen content in each sample was measured using a dissolved oxygen meter (INESA Scientific Instrument Co., Ltd, Shanghai, China). To further investigate the propulsion behavior of M-CaO₂-CL under different microenvironmental conditions, 20 mg of M-CaO₂-CL was dispersed in 20 mL of substrate solution under the following conditions: (i) PBS (pH 7.4), (ii) PBS (pH 6.0), (iii) PBS (pH 7.4) containing 100 µM H₂O₂, (iv) PBS (pH 6.0) containing 100 µM H₂O₂, (v) PBS (pH 6.0) containing 100 µM H₂O₂ with NIR irradiation (808 nm, 1.0 W/cm², 10 min), and (vi) PBS (pH 6.0) containing 100 µM H₂O₂ with NIR irradiation using M-CaO₂-CL nanomotors prepared with heat-inactivated CAT as a catalytic activity control. A schematic illustration of the ROS/pH-driven self-propulsion mechanism was generated based on the above experimental observations. Lignin release from M-CaO₂-CL was quantified using a UV–Vis spectrophotometer (Shimadzu, Japan). Briefly, M-CaO 2 -CL particles (1 mg/mL) were dispersed in (i) PBS (pH 7.4), (ii) PBS (pH 7.4) with NIR irradiation (808 nm, 1.0 W/cm², 10 min), (iii) PBS (pH 6.0) containing 100 µM H₂O₂, or (iv) PBS (pH 6.0) containing 100 µM H₂O₂ with NIR irradiation (808 nm, 1.0 W/cm², 10 min). At predetermined time points (0, 1, 2, 6, 12, 24, 36, 72 h), aliquots were collected and centrifuged to remove residual particles. The supernatants were analyzed spectrophotometrically to determine lignin concentration, and cumulative release was calculated accordingly. Bacterial culture S. gordonii (American Type Culture Collection, ATCC 10558) was cultured in Luria-Bertani (LB) broth (Hopebio, China) and LB agar plates at 37 °C under 5% CO₂. F. nucleatum (ATCC 25586) and P. gingivalis (ATCC 33277) were cultured in brain heart infusion (BHI) broth (Hopebio, China) and CDC anaerobic blood agar plates (Hopebio, China) at 37 °C under anaerobic conditions (80% N₂, 10% H₂, and 10% CO₂). Prior to use, the BHI medium was supplemented with vitamin K₁ (5 mg/L; Hopebio), L-cysteine hydrochloride (0.5 g/L; Solarbio), yeast extract (5 g/L; Solarbio), and hemin (5 mg/L; Hopebio). Antibacterial assays were conducted under 808 nm NIR irradiation (1 W/cm², 10 min) unless otherwise indicated. Antibacterial performance The antibacterial performance of the samples was evaluated using the plate-counting method. Briefly, 1 mL of logarithmic-phase bacterial suspension (1 × 10⁷ CFU/mL) of S. gordonii , F. nucleatum , and P. gingivalis was individually inoculated into 24-well plates. The samples were divided into ten groups: Control, Control + NIR, Lignin, Lignin + NIR, MPDA, MPDA + NIR, M-CaO₂, M-CaO₂ + NIR, M-CaO₂-CL, and M-CaO₂-CL + NIR. In the Lignin groups, the lignin concentration was equivalent to that loaded in M-CaO₂-CL, while the concentrations of all material groups were fixed at 100 µg/mL. The NIR+ groups were irradiated, whereas the NIR⁻ groups were kept in the dark. After treatment, all bacterial suspensions were incubated for an additional 2 h at 37 °C. Subsequently, 20 µL of each bacterial suspension (diluted 1:10 4 in PBS) was uniformly spread on agar plates and cultured for 48 h to count the number of bacterial colonies. The antibacterial rate (R, %) was calculated according to the following formula: where N₀ and N represent the CFU counts of the control and treated groups, respectively. Biofilm formation This study involving human saliva samples was approved by the relevant institutional medical ethics committee, and written informed consent was obtained from all donors prior to sample collection. Human saliva samples were collected from healthy adult volunteers. The pooled saliva was clarified by centrifugation (10,000 rpm, 10 min) and sterilized by filtration (0.22 μm) prior to use. To initiate biofilm formation, wells of a 24-well plate were first coated with sterile saliva and incubated for 24 h to allow the formation of an acquired pellicle. Equal volumes of S. gordonii , F. nucleatum , and P. gingivalis (1 × 10 7 CFU/mL each) were mixed, and 1 mL of the mixture was inoculated into each well. After 48 h of cultivation, mature multi-species bacterial biofilms were established. Anti-biofilm performance The mature biofilms were treated with four groups: (i) Control + NIR, (ii) MPDA + NIR, (iii) M-CaO 2 +NIR, and (iv) M-CaO 2 -CL + NIR (100 µg/mL) and subsequently incubated for 2 h. For crystal violet (CV) staining, the biofilms were fixed with methanol, stained with 400 µL of 0.25% CV solution for 20 min, and rinsed with PBS. The retained CV was dissolved in absolute ethanol, and absorbance at 570 nm was measured using a microplate reader (BioTek, USA) to quantify biomass. The total polysaccharide content of the biofilms was assessed using the sulfuric acid–phenol method. Briefly, treated biofilms were collected via ultrasonication, centrifugation, and resuspended in 1 mL of deionized water. Subsequently, 1 mL phenol solution (50 g/L) and 5 mL concentrated sulfuric acid were added. After 30 min of dark incubation, the absorbance of the supernatant was measured at 490 nm using a microplate reader. To visualize biofilm polysaccharides and bacterial nucleic acids, the samples were stained in the dark for 15 min using 4’,6-diamidino-2-phenylindole (DAPI), propidium iodide (PI), and wheat germ agglutinin (WGA), and then imaged by confocal laser scanning microscopy (CLSM, Zeiss LSM800, Germany). For live/dead bacterial staining, the samples were incubated with SYTO 9 (1 µM) and PI (5 µM) for 15 min in the dark, followed by CLSM observation to assess bacterial viability within the biofilms. Biofilm-associated protein leakage was quantified using the Bradford assay. In brief, 5 µL of supernatant from each group was transferred to a 96-well plate, mixed with 250 µL of Bradford reagent, and immediately measured for absorbance at 595 nm using a microplate reader. To assess surface morphology, treated biofilms were fixed with 4% paraformaldehyde for 30 min, then dehydrated through a graded ethanol series (30%, 50%, 70%, 80%, 95%, and 100%). The samples were sputter-coated with gold and observed via SEM. Anti-biofilm mechanism A hydrogen peroxide (H₂O₂) detection kit and a pH meter were used to detect the H 2 O 2 content and pH value of planktonic bacteria and bacterial biofilm. For planktonic bacteria, 2 mL mixed bacterial suspension was centrifuged. The pellet was resuspended in 5 mL saline and filtered (0.22 μm), and the H 2 O 2 concentration and pH value of the filtrate were determined. For bacterial biofilms, mature biofilms formed in 24-well plates were disrupted by sonication in an ultrasonic cleaning bath. The disrupted biofilm suspensions were collected, resuspended in 5 mL of sterile saline, filtered through a 0.22 μm membrane, and subsequently analyzed for H₂O₂ concentration and pH value. To evaluate the penetration capability of NPs, MPDA, M-CaO 2 -CL, and MPDA-CAT-Lignin (M-CaO 2 -CL without CaO₂) were labeled with Cy5 fluorescence dye (diluted 1:200 in PBS) and incubated in the dark for 30 min. Subsequently, NPs were washed with PBS and collected by centrifugation at 10,000 rpm for 10 min. Mature bacterial biofilms pre-stained with SYTO 9 were then treated with the Cy5-labeled NPs, and divided into NIR irradiation groups (MPDA + NIR, MPDA-CAT-Lignin + NIR and M-CaO₂-CL + NIR) and non-irradiation groups (MPDA, MPDA-CAT-Lignin and M-CaO₂-CL). After treatment, the biofilm penetration of NPs was then observed by CLSM. To separate the anti-biofilm contributions of photothermal and penetration effects, the mature biofilms were subjected to four treatments: MPDA, MPDA with NIR, MPDA-CAT-Lignin, MPDA-CAT-Lignin + NIR, M-CaO₂-CL, and M-CaO₂-CL with NIR. The samples in the NIR groups were irradiated and subsequently incubated for an additional 2 h. Then, 10 µL of CCK-8 reagent was added to each well and incubated for another 2 h in the dark. The absorbance at 450 nm was recorded using a microplate reader. The bacteria’s survival percentage was evaluated through live/dead staining. To further evaluate bacterial viability after treatment, an ATP luminescence assay was performed (Geruisi Biotechnology, Suzhou, China). Briefly, biofilms were scraped from the well surface and resuspended in PBS to obtain uniform bacterial suspensions. The suspensions were then centrifuged at 12,000 rpm for 5 min, and the resulting pellets were analyzed using an ATP Assay Kit (Geruisi Biotechnology, Suzhou, China) according to the manufacturer’s instructions. To evaluate the effect of photothermal treatment on catalase (CAT) stability, M-CaO₂-CL nanomotors (100 µg/mL) were subjected to NIR irradiation (808 nm, 10 min) in PBS (pH 7.4), while parallel samples without irradiation served as controls. After treatment, nanoparticles were collected by centrifugation (12,000 × g, 10 min), and CAT activity was determined using a catalase activity kit (Suzhou Grace Biotechnology, China) according to the manufacturer’s instructions. To further assess medium-dependent stability, nanoparticles were incubated for 12 h in different media, including PBS (pH 7.4), saline (0.9% NaCl), Dulbecco’s Modified Eagle Medium (DMEM), and acidic PBS (pH 6.0). After incubation, nanoparticles were collected by centrifugation under the same conditions, and CAT activity was measured using the same assay protocol. Cell culture Macrophage (RAW 264.7, ATCC) and osteoblast (MC3T3-E1, ATCC) were cultured with high-glucose Dulbecco’s modified Eagle’s medium (DMEM, Gibco, USA), added 10% fetal bovine serum (FBS, HyClone, USA), and 1% penicillin/streptomycin mixture (Gibco, USA) at 37 °C under a 5% CO 2 -containing atmosphere. Unless otherwise specified, NIR irradiation (808 nm, 1 W/cm², 10 min) was applied for the indicated experimental groups. Cell viability RAW 264.7 and MC3T3-E1 cells were separately seeded into 96-well plates at a density of 1 × 10⁴ cells per well and cultured for 24 h. The cells were then treated with different concentrations of M-CaO 2 -CL (50, 100, 200, and 400 µg/mL), and divided into NIR irradiation and non-irradiation groups. The cell viability was then detected by CCK-8 kit. Similarly, the viability of RAW 264.7 and MC3T3-E1 cells treated with different nanoparticles (MPDA, M-CaO₂, and M-CaO₂-CL; 100 µg/mL) was also assessed by CCK-8 assay. Briefly, at days 1, 3, and 5, 10 µL of CCK-8 reagent was added to each well, followed by incubation for 1 h. The supernatant was transferred to a new 96-well plate, and absorbance at 450 nm was measured using a microplate reader. Cell viability was calculated according to the following formula: A 0 , A C , and A represent the absorbance of blank, control, and experiment groups, respectively. For live/dead cell staining, RAW 264.7 and MC3T3-E1 cells were separately seeded in 24-well plates at 1 × 10⁴ cells/mL and cultured for 24 h. The cells were treated with MPDA, M-CaO₂, or M-CaO₂-CL (100 µg/mL) and divided into NIR irradiation and non-irradiation groups. After 24 h incubation, cells were stained with Calcein-AM/PI working solution for 30 min in the dark and observed using a fluorescence microscope (Zeiss, Germany). Antioxidant performance RAW 264.7 cells (3 × 10⁴ cells/mL) were cultured in 24-well plates for 24 h and treated with MPDA, M-CaO₂, or M-CaO₂-CL (100 µg/mL) followed by NIR irradiation (808 nm, 1 W/cm², 10 min). After incubation for 2 h, all groups except the control were stimulated with LPS (500 ng/mL). Intracellular ROS levels were detected using DCFH-DA (10 µM). Cells were incubated with the probe for 30 min, washed with PBS, and observed by fluorescence microscopy. For antioxidant gene analysis, RAW 264.7 cells were seeded in 6-well plates at 1 × 10⁵ cells/mL and treated as described above. After LPS stimulation for 24 h, total RNA was extracted using TRIzol reagent, reverse-transcribed into cDNA, and analyzed by qRT-PCR. The expression levels of Cat , Sod-1 , Nqo-1 , and HO-1 were quantified using primer sequences listed in Table S1. Anti-inflammatory performance RAW 264.7 cells were seeded in 6-well plates (1 × 10⁵ cells/mL) and cultured for 24 h. Cells were treated with MPDA, M-CaO₂, or M-CaO₂-CL (100 µg/mL), followed by NIR irradiation (808 nm, 1 W/cm², 10 min) and incubation for 2 h. Subsequently, all groups except the control were stimulated with LPS (500 ng/mL) for 24 h. For flow cytometry, cells were collected, resuspended in PBS containing 1% serum, and stained with anti-CD86 (0.25 µL) and anti-CD206 (0.5 µL) antibodies for 30 min on ice in the dark. After washing, cells were analyzed using a FACSVerse flow cytometer. Gene expression of iNOS , Tnf-α , Il-10 , and Tgf-β was evaluated by qRT-PCR using primers listed in Table S2. Cytokine secretion levels (iNOS, TNF-α, IL-10, and TGF-β) were quantified using ELISA kits according to the manufacturer’s instructions. Osteogenic differentiation To prepare macrophage-conditioned medium (CM), RAW 264.7 cells were seeded at 1 × 10⁵ cells/mL and treated with MPDA, M-CaO₂, or M-CaO₂-CL (100 µg/mL) followed by NIR irradiation and LPS stimulation as described above. Supernatants were collected at days 1, 3, 5, and 7 and mixed with α-MEM at a 1:1 ratio to obtain CM. MC3T3-E1 cells (5 × 10⁴ cells/mL) were cultured for 24 h and subsequently treated with CM-containing osteogenic induction medium. Osteogenic gene expression ( Opn , Runx-2 , Ocn , Col-1 ) was analyzed by qRT-PCR at day 7 using primers listed in Table S3. ALP staining and activity assays were performed at day 7, while mineralization was evaluated by Alizarin Red S staining at day 14. Quantification was performed by dissolving calcium nodules in 10% cetylpyridinium chloride and measuring absorbance at 562 nm. Immunoregulatory mechanism RAW 264.7 cells were seeded in 6-well plates at a density of 1 × 10⁵ cells/mL per well and cultured for 24 h. Cells were then treated with MPDA, M-CaO₂, or M-CaO₂-CL (100 µg/mL), followed by 808 nm NIR irradiation (1 W/cm², 10 min) and incubation for 2 h. Subsequently, all groups except the control were stimulated with lipopolysaccharide (LPS, 500 ng/mL) for 24 h. Total RNA was extracted from the LPS group and the M-CaO₂-CL + NIR group and subjected to transcriptome sequencing using the Illumina HiSeq X10 platform (Illumina, USA). Differentially expressed genes (DEGs) were identified based on a fold change > 1.5 or < − 1.5 with a p value < 0.05. Bioinformatics analyses were conducted using the Majorbio Cloud Platform. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was performed to identify biological processes associated with the DEGs, followed by gene set enrichment analysis (GSEA) to screen key immunoregulatory pathways. To further validate transcriptomic findings at the protein and cellular levels, RAW 264.7 cells were seeded in 24-well plates at a density of 3 × 10⁴ cells/mL (1 mL per well) and cultured for 24 h. Cells were treated with MPDA, M-CaO₂, or M-CaO₂-CL (100 µg/mL), followed by NIR irradiation (1 W/cm², 10 min) and incubation for 2 h. All groups except the control were subsequently stimulated with LPS (500 ng/mL) for 24 h. Cells were then fixed with 4% paraformaldehyde for 15 min, permeabilized using 0.25% Triton X-100 for 5 min, and blocked with 5 mg/mL bovine serum albumin (BSA) for 1 h at room temperature. The cells were incubated with an anti–HIF-1α primary antibody (1:200 dilution, 200 µL per well) at 4 °C overnight, followed by incubation with a fluorescent secondary antibody (1:200 dilution, 200 µL per well) for 1 h at room temperature. After washing with PBS, nuclei were counterstained with 4′,6-diamidino-2-phenylindole (DAPI). Fluorescence images were acquired using confocal laser scanning microscopy (CLSM) to evaluate intracellular HIF-1α expression and localization. Western blot analysis was performed to further assess the activation status of key inflammatory signaling pathways. RAW 264.7 cells were seeded in 6-well plates at a density of 1 × 10⁵ cells/mL and cultured for 24 h. Cells were treated with MPDA, M-CaO₂, or M-CaO₂-CL (100 µg/mL) followed by NIR irradiation (1 W/cm², 10 min) and incubation for 2 h. All groups except the control were subsequently stimulated with LPS (500 ng/mL) for 24 h. Total cellular proteins were extracted using RIPA lysis buffer (Millipore, USA), followed by sonication and centrifugation at 12,000 × g. Protein samples were separated by SDS–PAGE and transferred onto polyvinylidene fluoride (PVDF) membranes. Membranes were blocked with 5 mg/mL BSA for 2 h at room temperature and incubated with primary antibodies against TLR4, phosphorylated NF-κB (p-NF-κB), total NF-κB, and HIF-1α at 4 °C overnight. After washing, membranes were incubated with corresponding secondary antibodies for 2 h at room temperature. Protein bands were visualized using an enhanced chemiluminescence (ECL) detection kit (CWBIO, China) and quantitatively analyzed using Image-Pro Plus software (version 5.0, Media Cybernetics, USA). Animal model construction Male Sprague–Dawley (SD) rats (8 weeks old) were used in this study. All animal experimental procedures were approved by the relevant institutional Animal Ethics and Welfare Committee and conducted in accordance with the ARRIVE guidelines and the National Institutes of Health (NIH) Guide for the Care and Use of Laboratory Animals. All rats underwent extraction of the maxillary first molar followed by immediate implantation of a pure titanium implant (Φ 1.5 mm × 4.5 mm; Baoji Lianzhong Titanium Metal Materials Co., Ltd., China). The implants were sandblasted and acid-etched prior to use. Rats were anesthetized via intraperitoneal injection of pentobarbital sodium (50 mg/kg), and implants were placed into the extraction sockets under sterile conditions. Four weeks after implantation, rats were randomly divided into four groups ( n = 9 per group): (1) Control group, which received no further treatment after implantation; (2) Peri-implantitis group, in which peri-implantitis was induced by bacterial inoculation and subsequently treated with PBS; (3) Positive control group, in which peri-implantitis was induced and subsequently treated with minocycline hydrochloride (Mino); (4) M-CaO₂-CL group, in which peri-implantitis was induced and subsequently treated with M-CaO₂-CL followed by NIR irradiation (1 W/cm², 10 min). During bacterial inoculation and treatment, rats were anesthetized with isoflurane (2% in 100% oxygen). The peri-implantitis model was established by injecting a mixed bacterial suspension ( Streptococcus gordonii , Fusobacterium nucleatum , and Porphyromonas gingivalis ; 5 × 10⁷ CFU/mL) around the implants every 2 days for 10 days, resulting in successful model induction. In vivo therapeutic evaluation After successful peri-implantitis model establishment, rats were treated around the implants according to their assigned groups with PBS, M-CaO₂-CL, or Mino. Rats in the M-CaO₂-CL group received NIR irradiation (1 W/cm², 10 min) immediately after topical administration. Treatments were performed every two days for a total of 10 days. In vivo photothermal effects were monitored using an infrared thermal imaging system. To evaluate in vivo antibacterial efficacy, three rats from each group were euthanized one day after the final treatment. The implants were carefully retrieved from the maxillae and immersed in brain heart infusion (BHI) broth. After serial dilution, bacterial suspensions were plated on LB agar plates and CDC anaerobic agar plates, which were incubated under aerobic or anaerobic conditions, respectively. The number of bacterial colonies was counted to assess bacterial viability. At three days post-treatment, another three rats per group were sacrificed. The maxillae containing implants were harvested, fixed in 4% paraformaldehyde, and decalcified. Immunohistochemical staining for inducible nitric oxide synthase (iNOS), interleukin-10 (IL-10), and heme oxygenase-1 (HO-1) was performed to evaluate local immunomodulatory responses. Semi-quantitative analysis was conducted using ImageJ software. Based on previous studies assessing early osseointegration at comparable time points [ 51 , 52 ], rats were euthanized three weeks post-treatment, and implant-bearing maxillae were harvested and fixed for subsequent peri-implant bone integration analysis. Micro–computed tomography (micro-CT; Bruker, Germany) was used to assess bone integration at the bone–implant interface. Bone morphometric parameters, including bone volume/total volume (BV/TV) and trabecular number (Tb.N), were quantified using CTAn software (version 1.17, Bruker, Germany). Osteogenic outcomes were further evaluated by H&E staining and Masson’s trichrome staining. In vivo biosafety assessment To assess the photothermal biosafety of M-CaO₂-CL, the tongue and buccal mucosa of rats were treated with M-CaO₂-CL followed by 808 nm NIR irradiation (1 W/cm², 10 min). The treated tissues were collected one day after treatment and subjected to H&E staining to evaluate potential thermal injury. At three days post-treatment, blood samples were collected for complete blood count (CBC) analysis to assess systemic hematological parameters. At three weeks post-treatment, major organs including the heart, liver, spleen, lung, and kidney were harvested to evaluate long-term biosafety. All organs were fixed, processed, and analyzed by H&E staining. Statistical analysis All experiments were performed in triplicate, and data are presented as mean ± standard deviation (SD). Statistical analyses were performed using Student’s t-test or one-way analysis of variance (ANOVA), as appropriate. A value of p < 0.05 was considered statistically significant. Results and discussion Synthesis and characterization The microenvironment-responsive nanomotor (M-CaO₂-CL) was synthesized through a stepwise assembly process (Fig. 1 a). Brunauer–Emmett–Teller (BET) analysis confirmed that MPDA possessed a specific surface area of 33.75 m²/g (Fig. S1a), and Nonlocal Density Functional Theory/Grand Canonical Monte Carlo (NLDFT/GCMC) pore-size analysis revealed a dominant pore diameter of ~ 3.75 nm (Fig. S1b), validating its mesoporous architecture. MPDA nanoparticles were first deposited onto wax droplets to form MPDA@Wax templates, exhibiting a spherical morphology and rough surface texture (Fig. S2). CaO₂ NPs were then deposited on the exposed MPDA surface, and the wax was subsequently removed by chloroform dissolution to obtain Janus-structured M-CaO₂. Finally, CAT and lignin were co-loaded via a one-step adsorption process to yield the fully functional nanomotor, M-CaO₂-CL. Fig. 1. Open in a new tab Synthesis and characterization of M-CaO₂-CL nanomotors. ( a ) Schematic illustration of the fabrication process of M-CaO₂-CL nanomotor, including MPDA nanoparticle formation, CaO₂ loading, and catalase/lignin functionalization. ( b ) Transmission electron microscopy (TEM) images showing the morphology of MPDA, M-CaO₂, and M-CaO₂-CL nanoparticles (NPs) (scale bar: 100 nm). ( c ) Hydrodynamic size distributions measured by dynamic light scattering (DLS). ( d ) Zeta potentials of the nanoparticles. ( e ) Hydrodynamic size stability of M-CaO₂-CL nanoparticles measured by DLS at 0 h, after incubation in PBS (pH 7.4) for 48 h, and after incubation in acidic H₂O₂ buffer (100 µM H₂O₂, pH 6.0) for 48 h. ( f ) TEM image of M-CaO₂-CL nanoparticles with corresponding energy-dispersive X-ray spectroscopy (EDX) elemental mapping showing the spatial distribution of C, N, Ca, and O (scale bar: 100 nm). ( g ) Fourier transform infrared (FT-IR) spectra confirming chemical composition of MPDA, M-CaO₂, M-CaO₂-CL, lignin and CaO₂. ( h ) UV–vis absorption spectra of MPDA, M-CaO₂, M-CaO₂-CL, and lignin. ( i ) Photothermal heating curves of M-CaO₂-CL dispersion (100 µg/mL) under 808 nm near-infrared (NIR) irradiation at different laser power densities. ( j ) Temperature elevation profiles of M-CaO₂-CL dispersions at varying concentrations under 808 nm NIR irradiation (1 W/cm²). ( k ) Comparison of photothermal performance of MPDA, M-CaO₂, and M-CaO₂-CL nanoparticles under identical NIR irradiation conditions (808 nm, 1 W/cm²), showing temperature elevation profiles over irradiation time. (l ) Photothermal stability evaluated by three repeated laser on/off irradiation cycles TEM imaging showed that MPDA retained uniform spherical morphology with well-defined mesopores, whereas M-CaO₂ and M-CaO₂-CL exhibited partially coated surface features suggestive of CaO₂ deposition and subsequent biomolecule loading (Fig. 1 b). Energy-dispersive X-ray spectroscopy (EDX) mapping further verified the distribution of Ca within M-CaO₂-CL (Fig. 1 f). This asymmetry likely arises from the non-uniform internal distribution of CaO₂ within the porous MPDA framework, resulting in compositional heterogeneity rather than a sharply defined Janus interface or morphological phase separation. To further examine this asymmetric structure, additional HAADF-STEM imaging combined with elemental mapping was performed (Fig. S3), revealing spatially heterogeneous Ca distribution consistent with an internally distributed Janus-like architecture. Dynamic light scattering revealed increases in hydrodynamic diameter from 208.4 ± 3.5 nm (MPDA) to 264.7 ± 2.8 nm (M-CaO₂) and 258.4 ± 4.2 nm (M-CaO₂-CL), confirming successful surface modification (Fig. 1 c). The larger particle sizes measured by DLS compared with TEM images can be attributed to the intrinsic differences between dry-state TEM observation and hydrodynamic size measurements in aqueous dispersion. The polydispersity index (PDI) analysis revealed a low polydispersity index (PDI ≈ 0.03), indicated comparable dispersion homogeneity among the nanoparticles after surface modification (Fig. S4). The slight decrease in hydrodynamic diameter after CAT/lignin modification is minor and likely reflects changes in surface charge or dispersion state rather than structural shrinkage, consistent with the observed zeta potential variation. Correspondingly, zeta potentials shifted from − 11.6 ± 0.35 mV (MPDA) to − 8.8 ± 0.16 mV (M-CaO₂) and to − 10.3 ± 0.18 mV after CAT/lignin loading (Fig. 1 d), consistent with the introduction of CaO₂ and phenolic/hydroxyl-rich components. To assess microenvironment-responsiveness, M-CaO₂-CL was incubated for 48 h in PBS (pH 7.4) or an H₂O₂-containing acidic buffer (100 µM H₂O₂, pH 6). A modest size decrease occurred in PBS (246.8 ± 4.9 nm), whereas pronounced shrinkage was observed under acidic/oxidative conditions (207.8 ± 7.5 nm), consistent with CaO₂ decomposition and environment-triggered structural evolution (Fig. 1 e). Fourier-transform infrared (FT-IR) spectroscopy confirmed the presence of CaO₂ through the characteristic O–O stretching vibration associated with peroxide groups [ 53 ]. In addition, lignin incorporation was evidenced by its representative absorption bands at 1030 cm⁻¹ and 1265 cm⁻¹, corresponding to C–O deformation vibrations and guaiacyl (G) units, respectively, and a peak at 1595 cm⁻¹ attributed to aromatic skeletal vibrations (Fig. 1 g) [ 54 ]. UV–Vis spectra provided additional confirmation of lignin loading (Fig. 1 h). Quantitative analysis using standard calibration curves (Fig. S5) determined the loading contents of lignin and CAT to be 14.6% and 2.8%, respectively. Photothermal properties were next examined under 808 nm NIR irradiation. M-CaO₂-CL displayed power-dependent heating (0.5–1.5 W/cm², Fig. 1 i) and concentration-dependent temperature elevation (50–200 µg/mL, Fig. 1 j). At 100 µg/mL and 1.0 W/cm², MPDA, M-CaO₂, and M-CaO₂-CL reached steady-state temperatures of 48.7 °C, 48.1 °C, and 47.2 °C, respectively (Fig. 1 k), consistent with mild-PTT conditions. M-CaO₂-CL also maintained stable heating performance over repeated on/off cycles (Fig. 1 l). Based on cooling curves (Fig. S6a), the time constant (τs) and photothermal conversion efficiency (η) were calculated to be 136.94 s and 25.37%, respectively (Fig. S6b), confirming stable and reproducible photothermal responsiveness. Importantly, unlike many previously reported nanomotor systems that rely predominantly on external physical stimulation such as NIR irradiation for propulsion or therapeutic activation [ 55 , 56 ], the present design incorporates inflammation-associated microenvironmental cues, including elevated ROS levels and mildly acidic pH, as the primary activation signals. In this context, NIR irradiation serves mainly as a supplementary enhancer rather than the dominant driving factor. Such a design may improve pathological specificity while reducing reliance on exogenous stimulation. Motion behavior, dissolved oxygen generation, and drug release To clarify the mechanism underlying sustained nanomotor propulsion, the ROS/pH-responsive self-propulsion mechanism of M-CaO₂-CL nanomotors is schematically illustrated in Fig. 2 a, involving CAT-mediated H₂O₂ decomposition, acid-triggered CaO₂-derived H₂O₂ generation, and photothermal enhancement under NIR irradiation. Based on this mechanism, the motion behavior, dissolved oxygen generation, and drug release profile were further evaluated (Fig. 2 b–i). Fig. 2. Open in a new tab Motion behavior and drug release performance of M-CaO₂-CL nanomotors. ( a ) Schematic illustration of the ROS/pH-responsive self-propulsion mechanism of M-CaO₂-CL nanomotors, involving catalase-mediated H₂O₂ decomposition, acid-triggered CaO₂ hydrolysis generating additional H₂O₂, and photothermal enhancement under NIR irradiation. ( b ) Representative motion trajectories of MPDA, M-CaO₂, M-CaO₂-CL, and catalase-inactivated M-CaO₂-CL nanomotors under combined H₂O₂ (100 µM), mildly acidic pH (6.0), and NIR irradiation. ( c ) Mean square displacement (MSD) curves derived from trajectories in (b). ( d ) Quantified average velocities corresponding to (b). ( e ) Representative trajectories of M-CaO₂-CL nanomotors under different microenvironmental conditions: PBS (pH 7.4), acidic PBS (pH 6.0), H₂O₂ alone, H₂O₂ + pH 6.0, and H₂O₂ + pH 6.0 with NIR irradiation. ( f ) MSD curves corresponding to (e). ( g ) Average propulsion velocities under conditions shown in (e). ( h ) Dissolved oxygen generation profiles of M-CaO₂-CL nanomotors under various conditions, indicating catalase-mediated catalytic decomposition of H₂O₂ into O₂, including inactive-catalase controls. ( i ) Cumulative lignin release profiles of M-CaO₂-CL nanomotors under physiological (PBS pH 7.4 ± NIR) and inflammatory-mimicking conditions (H₂O₂ + pH 6.0 ± NIR). Error bars in panels c, d, f, g, h and i represent mean ± SD ( n = 3 independent experiments) The motility of the nanomotors was first evaluated in a simulated peri-implant inflammatory microenvironment (100 µM H₂O₂, pH 6.0) under NIR irradiation. As shown in Fig. 2 b–d, M-CaO₂ displayed moderately enhanced motion compared with MPDA, whereas M-CaO₂-CL displayed markedly increased trajectory lengths and mean square displacement (MSD), together with a significantly higher average propulsion velocity compared with the control groups. In addition, M-CaO₂-CL with inactive CAT showed substantially reduced motion, and lower propulsion velocity compared with nanomotors containing native active catalase, confirming the essential role of catalase activity in propulsion. These results suggest that the integration of CAT activity with pH-accelerated CaO₂ decomposition enables more efficient autonomous propulsion under pathological conditions. The measured velocity is consistent with the typical propulsion behavior reported for catalytic nanomotors under biochemical activation conditions [ 57 , 58 ]. To clarify the contribution of individual microenvironmental cues, the motion of M-CaO₂-CL was examined under different conditions (Fig. 2 e–g). Limited motility was observed in physiological PBS (pH 7.4), whereas the presence of H₂O₂ effectively initiated nanomotor motion. Acidic pH (6.0) further enhanced trajectory lengths, and the strongest propulsion occurred under the combined H₂O₂ + pH 6.0 condition, with additional enhancement upon NIR irradiation. The corresponding MSD curves and quantified velocity data showed consistent trends, supporting the interpretation that H₂O₂ serves as the primary substrate for O₂ generation, while acidic pH accelerates CaO₂ decomposition to replenish H₂O₂ and thereby sustain nanomotor motion [ 59 ]. Mild photothermal heating provides an additional boost to motion [ 60 ]. To address the sustainability of nanomotor propulsion, Ca²⁺ release from M-CaO₂-CL nanomotors was quantified under inflammation-mimicking acidic H₂O₂ conditions as an indirect indicator of CaO₂ decomposition (Fig. S7). The gradual Ca²⁺ release profile indicates progressive CaO₂ consumption over extended periods rather than rapid exhaustion, suggesting sustained substrate availability for CAT-mediated H₂O₂ decomposition and O₂-driven propulsion. To examine whether CaO₂ decomposition affects photothermal performance, temperature elevation of M-CaO₂-CL nanomotors was measured under acidic/oxidative conditions and repeated NIR on/off irradiation cycles (Fig. S8). Comparable temperature increases without attenuation during repeated cycles indicate preserved photothermal conversion of the MPDA shell, suggesting that CaO₂ decomposition mainly reflects fuel consumption and payload release rather than deterioration of the photothermal core. To elucidate the propulsion mechanism, dissolved O₂ generation was quantified under various conditions (Fig. 2 h). M-CaO₂-CL generated substantially higher O₂ levels in the presence of H₂O₂ than in PBS, confirming CAT-mediated H₂O₂ decomposition as the primary source of propulsive oxygen. Notably, nanomotors containing inactive CAT produced less O₂ than those containing active CAT under the same H₂O₂ + pH 6.0 + NIR conditions, further supporting the indispensable role of catalase activity in propulsion. Under acidic conditions, CaO₂ decomposition supplied additional H₂O₂, which in turn sustained O₂ generation over time. NIR irradiation further increased O₂ production, consistent with photothermally enhanced catalytic kinetics reported previously [ 61 ]. Collectively, these results support a ROS/pH-responsive propulsion mechanism, in which ROS-triggered oxygen generation is functionally coupled with pH-accelerated CaO₂ decomposition, thereby sustaining nanomotor propulsion. Lignin release from M-CaO₂-CL was subsequently evaluated under different microenvironmental conditions (Fig. 2 i). Compared with PBS, cumulative lignin release was substantially increased under H₂O₂ + pH 6.0 conditions, consistent with microenvironment-responsive structural evolution and accelerated payload liberation. NIR irradiation resulted in a slight additional increase, likely due to thermally facilitated diffusion. Collectively, these findings demonstrate that M-CaO₂-CL integrates inflammatory microenvironment–responsive propulsion with microenvironment-triggered lignin release, enabling coordinated activation of both nanomotor motion and therapeutic payload release under peri-implant inflammatory conditions. Compared with previously reported photothermal- or ROS-amplifying antibacterial nanoplatforms [ 19 , 55 ], this system emphasizes pathology-driven propulsion coupled with intrinsic anti-inflammatory modulation rather than primary dependence on external activation or ROS overproduction. This strategy may be particularly advantageous for inflammatory diseases such as peri-implantitis, where excessive oxidative stress could otherwise exacerbate tissue inflammation. In vitro anti-biofilm efficacy Bacterial biofilms represent a major pathogenic factor in peri-implantitis. S. gordonii acts as an early colonizer, F. nucleatum functions as a bridging species, and P. gingivalis is a key periopathogen [ 62 – 64 ]. These three species were therefore used to evaluate the antibacterial and anti-biofilm performance of M-CaO₂-CL. Antibacterial activity was first examined with or without NIR irradiation. As shown in Fig. S9 and Fig. 3 a, lignin, MPDA, M-CaO₂, and M-CaO₂-CL showed minimal antibacterial effects under dark conditions. Under NIR irradiation, MPDA and M-CaO₂ exhibited enhanced antibacterial activity attributable to their photothermal effects. Notably, only the M-CaO₂-CL + NIR group achieved near-complete bacterial eradication, with inhibition rates of 97.3%, 97.3%, and 98.2% against S. gordonii , F. nucleatum , and P. gingivalis , respectively. Fig. 3. Open in a new tab Anti-biofilm efficacy of M-CaO₂-CL nanomotors. ( a ) Survival rates of representative oral biofilm-forming bacteria ( S. gordonii , F. nucleatum , and P. gingivalis ) after the indicated treatments. ( b ) Crystal violet staining images showing total residual biofilm biomass. ( c ) Quantitative analysis of biofilm biomass based on crystal violet absorbance. ( d ) Quantification of extracellular polysaccharide content within biofilms. ( e ) Confocal laser scanning microscopy (CLSM) images showing extracellular polymeric substance (EPS) components after treatment: dead bacteria stained with propidium iodide (PI, red), polysaccharides labeled with WGA-FITC (green), and extracellular DNA stained with DAPI (blue) (scale bar: 40 μm) Mechanistically, this antibacterial performance is primarily associated with catalase (CAT)-driven O₂ propulsion rather than direct H₂O₂-mediated sterilization. Specifically, CAT catalyzes the decomposition of pathologically elevated endogenous H₂O₂ into O₂, generating autonomous nanomotor motion that enhances penetration into dense biofilms. Meanwhile, mildly acidic conditions promote CaO₂ decomposition, helping sustain the local H₂O₂ substrate pool required for continuous CAT-driven propulsion. Under NIR irradiation, mild photothermal heating further improves biofilm permeability and bacterial exposure, collectively accounting for the near-complete bacterial eradication observed in the M-CaO₂-CL + NIR group. We next assessed antibiofilm performance. Crystal violet staining (Fig. 3 b–c) revealed that M-CaO₂-CL + NIR produced the greatest reduction in biofilm biomass. Extracellular polysaccharide quantification (Fig. 3 d) further confirmed marked EPS depletion following M-CaO₂-CL + NIR treatment. CLSM imaging (Fig. 3 e) revealed markedly reduced EPS signals (WGA-FITC), decreased extracellular DNA (DAPI), and widespread bacterial death (PI) in the M-CaO₂-CL + NIR group, suggesting EPS structural alteration, although direct mechanical disruption was not directly visualized. Live/dead staining confirmed the antibiofilm effects (Fig. S10a–c). Untreated biofilms showed dense viable bacteria, whereas MPDA + NIR and M-CaO₂+NIR increased bacterial death and reduced thickness. M-CaO₂-CL + NIR yielded the most extensive PI-positive signals and the thinnest biofilm. Protein leakage (Fig. S11a) and SEM imaging (Fig. S11b) supported this trend: M-CaO₂-CL + NIR induced the highest protein release and the most severe morphological damage, including membrane collapse and structural fragmentation. In vitro anti-biofilm mechanisms Under the simulated inflammatory microenvironment, ROS mainly originates from activated inflammatory immune cells (e.g., LPS-induced M1 macrophages) with additional contributions from bacterial metabolism within biofilms. Analysis of the biofilm microenvironment revealed H₂O₂ levels of 17.0 µM (planktonic) and 53.3 µM (biofilm) (Fig. 4 a), along with pH values of 6.97 and 5.88 (Fig. S12), thereby providing a ROS-enriched and mildly acidic microenvironment favorable for ROS/pH-responsive nanomotor propulsion. Confocal imaging of Cy5-labeled nanoparticles showed limited penetration of MPDA, reaching 5.3 μm without NIR and 6.8 μm with NIR. Similarly, M-CAT-Lignin (lacking CaO₂-driven propulsion) exhibited shallow penetration depths of 4.6 μm without NIR and 7.6 μm with NIR. In contrast, M-CaO₂-CL penetrated significantly deeper, reaching 20.1 μm without NIR and 24 μm with NIR (Fig. 4 b–c). Fig. 4. Open in a new tab Mechanisms underlying antibiofilm activity of M-CaO₂-CL nanomotors. ( a ) Measured H₂O₂ concentrations in planktonic bacterial cultures and mature biofilms. ( b ) Quantitative analysis of nanoparticle penetration depth derived from CLSM Z-stack images. ( c ) Representative Z-stack CLSM images showing nanoparticle penetration (red fluorescence) into biofilms labeled in green. ( d ) Live/dead staining images of biofilm bacteria after different treatments (live bacteria: green; dead bacteria: red). ( e ) Quantitative analysis of viable bacterial percentage from ( d ). ( f ) CCK-8 assay evaluating metabolic activity of biofilm bacteria after treatment. ( g ) Schematic illustration summarizing the antibiofilm mechanism of M-CaO₂-CL nanomotors, including ROS/pH-driven propulsion, enhanced penetration into biofilms, photothermal effects under NIR irradiation, and subsequent biofilm disruption and bacterial eradication Although continuous long-term tracking of individual nanomotors was not performed, the observed penetration depth (~ 24 μm) suggests sustained propulsion beyond the short observation window in Fig. 2 . Despite the relatively thin in vitro biofilm model compared with some clinically reported mature biofilms (> 50 μm), these results still support effective propulsion-driven biofilm infiltration. Consistent with this observation, CaO₂ decomposition under acidic conditions appears to dominate nanomotor propulsion and biofilm penetration, whereas photothermal therapy (PTT) provides a secondary enhancement. These findings highlight the importance of propulsion-enabled transport in overcoming diffusion limitations within dense biofilms. Live/dead staining further confirmed the antibacterial efficacy (Fig. 4 d–e). In the absence of NIR irradiation, MPDA did not exhibit antibacterial properties, M-CAT-Lignin reduced the proportion of viable bacteria to 94.2%, while M-CaO₂-CL reduced the proportion of viable bacteria to 84.1%, likely attributable to propulsion-assisted penetration and improved nanomotor penetration within the biofilm matrix. Under NIR irradiation, MPDA decreased bacterial viability to 44.7%, whereas M-CAT-Lignin reduced viability to 45%. Notably, M-CaO₂-CL + NIR further reduced viability to 2%, indicating a pronounced synergistic bactericidal effect arising from the combination of mild photothermal disinfection and propulsion-enhanced bacterial exposure. Consistently, CCK-8 assays revealed the lowest bacterial metabolic activity in the M-CaO₂-CL + NIR group (Fig. 4 f). ATP-based viability assays further corroborated these findings, providing a more direct quantification of viable bacterial biomass and showing trends consistent with the CCK-8 results (Fig. S13). Collectively, these results demonstrate that M-CaO₂-CL achieves superior antibiofilm efficacy under NIR irradiation through the integration of mild photothermal disinfection and propulsion-enabled transport (Fig. 4 g). The mild temperature elevation (< 48 °C) alone is insufficient for rapid bactericidal effects, suggesting that the pronounced antibacterial enhancement primarily arises from synergistic propulsion-facilitated penetration and photothermal stimulation within the dense biofilm matrix. Although the 48-h biofilm represents an early-to-intermediate in vitro stage without extensive mineralization [ 65 , 66 ], these findings nevertheless support effective antibiofilm activity. Given the dynamic and non-sealed peri-implant microenvironment, the moderate and transient O₂ generation is expected to alleviate local hypoxia without inducing hyperoxia-related adverse effects or gas accumulation. To assess whether photothermal treatment affects catalytic functionality, CAT activity was measured after NIR irradiation (808 nm, 10 min) (Fig. S14). Approximately 85% of the initial activity was retained despite the temperature increase (~ 48 °C), indicating good enzymatic stability sufficient to support H₂O₂ decomposition and nanomotor propulsion. Stability tests in PBS (pH 7.4), saline, DMEM, and acidic PBS (pH 6.0) showed largely preserved activity under neutral conditions, with a moderate decrease (~ 75% retained) under acidic conditions (Fig. S15), consistent with the known acid sensitivity of catalase. In vitro antioxidant, anti-Inflammatory, and osteogenic differentiation effects The cytocompatibility of the nanomotors was first evaluated in RAW 264.7 macrophages. As shown in Fig. S16a–b, M-CaO₂-CL at 50–100 µg/mL exhibited good viability under dark conditions, while higher concentrations (200–400 µg/mL) caused a dose-dependent decrease on day 1. Under NIR irradiation, 100 µg/mL M-CaO₂-CL induced only a transient decrease in viability that recovered by day 3, whereas 200–400 µg/mL caused irreversible cytotoxicity due to excessive heating. Material-dependent comparisons (Fig. S16c–e) confirmed that MPDA, M-CaO₂, and M-CaO₂-CL maintained high biocompatibility at 100 µg/mL, with or without NIR. A similar trend in MC3T3-E1 osteoblasts (Fig. S17) further verified the cytocompatibility of the nanoplatform at the selected working concentration. Chronic biofilm-induced inflammation promotes sustained M1 polarization and excessive ROS generation, thereby disrupting immune homeostasis and impairing tissue repair [ 67 , 68 ]. Thus, reducing oxidative stress and reprogramming macrophage inflammation are essential for restoring a pro-regenerative microenvironment. DCFH-DA staining (Fig. 5 a–b) showed that LPS markedly increased intracellular ROS, whereas MPDA and M-CaO₂ reduced ROS signals, consistent with the intrinsic radical-scavenging activity of MPDA and the H₂O₂-consuming effect of CaO₂. Notably, M-CaO₂-CL produced the most pronounced ROS reduction. Consistently, qPCR analyses of antioxidant genes (Fig. 5 c–f) showed that M-CaO₂-CL induced the highest expression of Cat , Sod-1 , Nqo-1 , and HO-1 , indicating strengthened antioxidant responses. Fig. 5. Open in a new tab Antioxidant, anti-inflammatory, and osteogenic-promoting effects of M-CaO₂-CL nanomotors. ( a ) Fluorescence imaging of intracellular ROS levels in macrophages stained with DCFH-DA (green fluorescence indicates ROS). ( b ) Semi-quantitative analysis of intracellular ROS fluorescence intensity. ( c–f ) qPCR analysis of antioxidant gene expression ( Cat , Sod-1 , Nqo-1 , HO-1 ) in macrophages. ( g , h ) Flow cytometry histograms and quantitative analysis of M1 macrophage markers (CD86⁺). ( i , j ) Flow cytometry histograms and quantitative analysis of M2 macrophage markers (CD206⁺). ( k–n ) qPCR analysis of pro-inflammatory ( iNOS , Tnf-α ) and anti-inflammatory ( Il-10 , Tgf-β ) cytokine gene expression in macrophages. ( o ) Alkaline phosphatase (ALP) staining of MC3T3-E1 osteoblasts cultured with macrophage-conditioned medium (CM) from different treatment groups. ( p ) Alizarin Red S (ARS) staining indicating mineralization matrix formation after 14 days of osteogenic induction. (* P < 0.05, ** P < 0.01, *** P < 0.001, **** P < 0.0001; ns, not significant) The antioxidant activity of MPDA and lignin is largely attributed to their catechol-rich polyphenolic structures, which enable efficient radical scavenging through electron-donating reactions [ 69 , 70 ]. Accordingly, the superior antioxidant performance of M-CaO₂-CL likely arises from combined antioxidative mechanisms, including direct radical scavenging by MPDA and lignin, together with catalase (CAT)-mediated enzymatic decomposition of H₂O₂ into O₂ and H₂O. Flow cytometry (Fig. 5 g–j) revealed that M-CaO₂-CL most effectively decreased CD86⁺ M1 macrophages and increased CD206⁺ M2 macrophages. This trend was supported by gene expression analysis (Fig. 5 k–n) and ELISA measurements (Fig. S18), showing downregulation of pro-inflammatory mediators (iNOS, TNF-α) and upregulation of IL-10 and TGF-β in the M-CaO₂-CL group. Previous studies have reported that MPDA can inhibit inflammation and promote macrophage polarization toward an M2 phenotype [ 71 , 72 ], while lignin and its derivatives reduce inflammatory cell infiltration and facilitate M2 macrophage polarization [ 73 ]. Therefore, the pronounced anti-inflammatory and immunomodulatory effects of M-CaO₂-CL likely result from the combined actions of MPDA and lignin. Similar multifunctional nano-systems have been reported to integrate ROS modulation with immunoregulatory functions through multiple interacting mechanisms [ 74 – 77 ], providing useful insights into nano-enabled immune regulation in pathological microenvironments. In this context, the combined presence of MPDA, lignin, and CAT may contribute to the observed antioxidant and macrophage immunomodulatory functions of M-CaO₂-CL. Given that immune homeostasis is essential for osteogenesis [ 78 ] and macrophages critically shape osteogenic microenvironments [ 79 , 80 ], macrophage-conditioned medium (CM) was used to assess downstream osteogenic responses. As shown in Fig. S19, CM from normal macrophages enhanced osteogenic gene expression ( Col-1 , Runx-2 , Opn , Ocn ), whereas CM from LPS-stimulated macrophages (LPS@CM) markedly suppressed these markers. CM derived from MPDA- or M-CaO₂-treated macrophages partially restored osteogenic gene expression, while M-CaO₂-CL@CM produced the strongest upregulation across all osteogenic markers. Osteogenic function was further confirmed by ALP staining (Fig. 5 o) and ALP activity quantification (Fig. S20a). Alizarin red staining (Fig. 5 p) and mineralization analysis (Fig. S20b) revealed the greatest calcium nodule formation in the M-CaO₂-CL@CM group after 14 days. Collectively, these findings indicate that M-CaO₂-CL may alleviate oxidative stress and inflammatory responses primarily through coordinated antioxidant and immunomodulatory mechanisms, promotes macrophage polarization toward an anti-inflammatory M2 phenotype, and enhances downstream osteogenic differentiation, highlighting its potential to help restore an immune-regenerative microenvironment under inflammatory conditions. Immunoregulatory mechanisms To elucidate how M-CaO₂-CL modulates inflammatory signaling, transcriptomic profiling was performed in LPS-stimulated RAW264.7 macrophages with or without M-CaO₂-CL under NIR irradiation. The heatmap (Fig. 6 a) revealed distinctly altered transcriptional landscapes between the two groups, indicating broad immunomodulatory reprogramming. Volcano plot analysis (Fig. 6 b) identified 2,525 downregulated and 2,441 upregulated genes following M-CaO₂-CL + NIR treatment. Fig. 6. Open in a new tab Molecular mechanisms underlying antioxidant and anti-inflammatory effects of M-CaO2-CL. ( a ) Heatmap of differentially expressed genes (DEGs) comparing LPS-stimulated macrophages with LPS + M-CaO₂-CL + NIR treatment. ( b ) Volcano plot showing significantly upregulated and downregulated DEGs. ( c ) KEGG pathway annotation of DEGs. ( d ) KEGG enrichment analysis highlighting major biological pathways modulated by M-CaO₂-CL treatment. ( e–h ) Gene set enrichment analysis (GSEA) demonstrating downregulation of HIF-1, Toll-like receptor, TNF, and NOD-like receptor signaling pathways. ( i ) Immunofluorescence staining of HIF-1α expression in macrophages. ( j ) Western blot analysis of TLR-4, pNF-κB, NF-κB, and HIF-1α protein expression. ( k ) Schematic illustration of the proposed molecular mechanisms by which M-CaO₂-CL inhibits HIF-1α and NF-κB signaling pathways KEGG classification (Fig. 6 c) showed that differentially expressed genes were distributed across pathways related to immune regulation, inflammation, metabolism, and oxidative stress–associated processes. KEGG enrichment analysis (Fig. 6 d) further highlighted oxidative phosphorylation, ROS-related carcinogenesis, and TNF signaling among the key pathways modulated by M-CaO₂-CL. Gene Set Enrichment Analysis (GSEA) suggested downregulation of the hypoxia inducible factor-1 (HIF-1), Toll-like receptor (TLR), tumor necrosis factor (TNF), and NOD-like receptor (NLR) signaling pathways (Fig. 6 e–h), all of which are central regulators of macrophage-mediated inflammation. These transcriptomic findings suggest pathway-level associations with inflammatory modulation rather than definitive causal mechanistic evidence. Mechanistically, excessive ROS can stabilize HIF-1α during chronic inflammation, promoting iNOS expression, M1 polarization, and amplified cytokine release [ 81 ]. TLR signaling activates NF-κB in response to microbial ligands [ 82 ], while TNF signaling stimulates NF-κB through TRADD-dependent kinase cascades [ 83 ]. NLR activation similarly triggers NF-κB upon sensing intracellular danger signals [ 84 ]. NF-κB can also enhance HIF-1α transcription, forming a positive feedback loop that exacerbates inflammatory responses [ 85 ]. Cluster analysis was further performed to investigate genes associated with the HIF-1 and NF-κB signaling pathways. The HIF family comprises heterodimeric transcription factors consisting of an oxygen-regulated α-subunit (HIF-1α) and a constitutive β-subunit (HIF-1β/Arnt), with Hif-1α representing the most functionally prominent member [ 86 ]. Under normoxic conditions, HIF-1α undergoes rapid proteasomal degradation; however, LPS stimulation suppresses this degradation, thereby facilitating the assembly of the HIF-1α–HIF-1β–p300 transcriptional complex. This complex binds to hypoxia-response elements (HREs) and promotes the transcription of glycolytic and pro-inflammatory genes, contributing to M1 macrophage polarization [ 81 , 87 ]. In parallel, LPS activates the Toll-like receptor 4 (TLR4)–MyD88–IRAK–TRAF6 signaling cascade, leading to phosphorylation of the IKK complex and subsequent nuclear translocation of NF-κB (p65). Activated NF-κB then induces the expression of pro-inflammatory mediators, including chemokines such as Ccl4 and Cxcl2 [ 88 ]. Consistent with this these established mechanism, transcriptomic analysis suggested reduced expression of multiple genes involved in the HIF-1 signaling pathway, including Hif-1α , Hif-1β , Ep300 , and key glycolysis-related genes ( Slc2a1 , Hk1-3 , Pdk1 , Pfkl , and Eno3 ) (Fig. S21a). Similarly, genes associated with NF-κB signaling—namely Tlr4 , Myd88 , Irak1/4 , Traf6 , Table 1/2/3 , Ikkα/Ikk1 ( Chuk ), Ikkβ / Ikk2 ( Ikbkb ), p65 ( Rela ), Nfkb1 , Ccl4 , Cxcl2 —were appeared downregulated following M-CaO₂-CL treatment compared with the LPS group (Fig. S21b). Immunofluorescence staining confirmed that LPS markedly increased HIF-1α expression, whereas treatment with MPDA and M-CaO₂ partially attenuated this effect. Notably, M-CaO₂-CL produced the most pronounced reduction in HIF-1α expression (Fig. 6 i and Fig. S22). Western blot analysis corroborated these findings, demonstrating decreased expression of Hif-1α, TLR4, and phosphorylated NF-κB (pNF-κB) in the M-CaO₂-CL group (Fig. 6 j). Previous studies have shown that MPDA may suppress inflammation through modulation of NF-κB signaling [ 89 ] and downregulation of HIF-1α expression via H₂O₂ decomposition [ 90 , 91 ]. Similarly, lignin and its derivatives suppress pro-inflammatory cytokines (IL-6, TNF-α, IL-1β, iNOS), reduce inflammatory cell infiltration, and promote M2 macrophage polarization, likely mediated through inhibition of NF-κB signaling [ 73 , 92 – 94 ]. Lignin derivatives have also been reported to attenuate NF-κB-dependent osteoclast differentiation and inflammatory signaling [ 95 ] and may additionally regulate HIF-1α-related pathways [ 96 ]. Consistent with these reports, our results suggest that the immunoregulatory effects of M-CaO₂-CL may arise from the combined functions of MPDA and lignin. The potential mechanism appears to involve attenuation of HIF-1α- and NF-κB-associated inflammatory signaling, which may contribute to macrophage anti-inflammatory reprogramming. However, definitive causal relationships require further targeted mechanistic investigation. A schematic illustration summarizing the proposed molecular mechanisms is presented in Fig. 6 k. In vivo therapeutic effects of M-CaO 2 -CL for peri-implantitis The therapeutic efficacy of M-CaO₂-CL for peri-implantitis was evaluated in a rat model following the workflow outlined in Fig. 7 a. Titanium implants (Φ1.5 mm × 4.5 mm) with an SLA-treated surface (Fig. S23a–b) were placed immediately after extraction of the maxillary first molar (Fig. S23c). Four weeks after implantation, healthy peri-implant tissues exhibited normal mucosal appearance (Fig. S24a) and dense trabecular bone surrounding the implant on micro-CT (Fig. S24b). H&E staining further confirmed intact peri-implant bone and minimal inflammation (Fig. S24c), indicating successful primary osseointegration. Fig. 7. Open in a new tab In vivo therapeutic evaluation of M-CaO 2 -CL nanomotors in peri-implantitis. ( a ) Schematic overview of the experimental workflow, including peri-implantitis model establishment, treatment administration, and evaluation procedures. ( b ) Representative infrared thermal images of the maxilla during NIR irradiation in control and M-CaO₂-CL–treated rats. ( c ) Temperature elevation curve of the maxillary region under NIR irradiation. ( d ) Representative aerobic and anaerobic bacterial colonies recovered from implant surfaces after treatment. ( e ) Quantification of bacterial colony-forming units (CFUs). ( f–g ) Immunohistochemical staining and semi-quantitative analysis of inflammatory markers iNOS, IL-10, and HO-1 in peri-implant tissues. ( h ) Representative three-dimensional micro-CT reconstructions of peri-implant bone in each group. ( i–j ) Quantitative micro-CT analysis of bone morphometric parameters, including bone volume fraction (BV/TV) and trabecular number (Tb.N). ( k ) Histological evaluation of peri-implant bone after 3-week treatment using H&E staining and Masson’s trichrome staining. (* P < 0.05, ** P < 0.01, *** P < 0.001, **** P < 0.0001; ns, not significant) A peri-implantitis model was then established by inoculation with a mixed suspension of S. gordonii , F. nucleatum , and P. gingivalis . Ten days later, rats exhibited gingival redness and swelling (Fig. S24d), marked bone loss on micro-CT (Fig. S24e), and inflammatory cell infiltration on histology (Fig. S24f), confirming successful model induction. Corresponding healthy controls showed intact gingiva and bone with minimal inflammatory infiltration (Fig. S24g–i). Quantitative analysis (BV/TV, Tb.Th, Tb.N) further validated significant bone loss in the peri-implantitis group (Fig. S24j). After model confirmation, rats received topical M-CaO₂-CL treatment, with minocycline (Mino) serving as a positive control, followed by NIR irradiation. Infrared thermal imaging showed that the peri-implant region reached ~ 48 °C at 10 min (Fig. 7 b–c), remaining within the mild-PTT range. Because bacterial colonization drives peri-implantitis progression [ 97 ], in vivo antibacterial performance was examined. As shown in Fig. 7 d–e, peri-implantitis rats displayed abundant aerobic and anaerobic colonies, whereas M-CaO₂-CL and Mino markedly reduced bacterial loads to near-healthy levels, indicating robust antibacterial efficacy. To evaluate immunomodulation, iNOS, IL-10, and HO-1 expression was assessed by immunohistochemistry. Compared with untreated peri-implantitis tissues, both Mino and M-CaO₂-CL reduced iNOS⁺ cells and increased IL-10 and HO-1 expression (Fig. 7 f–g). Notably, M-CaO₂-CL produced the most pronounced suppression of iNOS and the strongest upregulation of IL-10 and HO-1, consistent with its antioxidative and anti-inflammatory effects observed in vitro. Given that chronic inflammation compromises peri-implant bone maintenance and repair, micro-CT was performed 3 weeks post-treatment. Untreated peri-implantitis rats exhibited compromised peri-implant bone structure, whereas Mino and M-CaO₂-CL groups showed substantial recovery (Fig. 7 h). Quantitative analysis confirmed significant increases in BV/TV and Tb.N in the M-CaO₂-CL group (Fig. 7 i–j). Histological staining further supported these findings: peri-implantitis tissues showed fibrous tissue encapsulation and disrupted collagen, whereas M-CaO₂-CL promoted more organized collagen deposition and evident new bone formation at the bone–implant interface (Fig. 7 k). Biosafety analysis demonstrated that topical M-CaO₂-CL with NIR irradiation did not induce mucosal irritation (thermal imaging and H&E, Fig. S25). Complete blood count (CBC) parameters remained within normal ranges (Fig. S26), and histological examination of major organs revealed no pathological abnormalities (Fig. S27), confirming favorable local and systemic biosafety. MPDA is a melanin-like bioinspired polymer with favorable biocompatibility. Previous studies have demonstrated good biosafety and emerging biodegradability of MPDA-based nanomaterials, although long-term degradation remains to be fully clarified [ 98 – 100 ]. Consistent with these reports, our findings further support its favorable safety profile and potential for clinical translation. Conclusion In this study, we developed a microenvironment-responsive nanomotor (M-CaO₂-CL) that integrates antibiofilm activity with immunomodulatory functionality for the treatment of peri-implantitis. Upon NIR irradiation, M-CaO₂-CL exhibited efficient biofilm disruption and bacterial eradication through the coordinated action of autonomous propulsion and mild photothermal disinfection. Beyond its antibacterial effects, the nanomotor effectively alleviated oxidative stress and inflammatory responses, likely through suppression of the HIF-1α and NF-κB signaling pathways. In a rat peri-implantitis model, topical application of M-CaO₂-CL under NIR irradiation significantly reduced bacterial burden and attenuated local inflammation, contributing to the preservation of peri-implant bone architecture. Collectively, this work demonstrates a multifunctional nanomotor that combines inflammatory microenvironment–responsive activation, enhanced biofilm penetration, mild photothermal disinfection, and immune regulation, offering a promising therapeutic platform for managing biofilm-associated peri-implantitis. Supplementary Information Below is the link to the electronic supplementary material. Supplementary Material 1 (1,017KB, mp4) Supplementary Material 2 (39.1MB, docx) Acknowledgements We sincerely thank Sanwen Li, Muxiang Wang, Deyu Fan, and Yiyang Wei from the Stomatological Hospital of Tianjin Medical University for their valuable assistance and support during the preparation of this manuscript. Author contributions WW and JY: Data curation, Formal analysis, Investigation, Validation, Visualization, Writing – Original Draft. LN: Data curation, Investigation, Methodology, Validation. Yunkai Liang: Data curation, Investigation, Methodology. YT: Investigation, Writing – Original Draft. NW: Data curation, Investigation, Validation. YS: Writing – Original Draft. BC: Conceptualization, Funding acquisition, Supervision, Writing – Review & Editing. HB: Conceptualization, Project administration, Supervision, Writing – Review & Editing. Ying Li: Conceptualization, Data curation, Funding acquisition, Investigation, Project administration, Supervision, Writing – Review & Editing. All authors have read and approved the final manuscript. Funding This work was funded by the National Natural Science Foundation of China (Grant No. 82171008); Tianjin Science and Technology Planning Project (Grant No. 24JCYBJC01060); Tianjin Key Medical Discipline Construction Project (Grant No. TJYXZDXK-3-008B); Tianjin Health Research Project (Grant No. TJWJ2024MS010). Data availability The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Declarations Ethics approval and consent to participate This study involving human saliva samples was approved by the Medical Ethics Committee of Tianjin Medical University Stomatological Hospital (Approval No. TMUhMEC20231201), and written informed consent was obtained from all donors. All animal experiments were approved by the Animal Ethical and Welfare Committee of Tianjin Nankai Hospital (Ethics Approval No. NKYY-DWLL-2024-063) and conducted in accordance with relevant ethical guidelines. Consent for publication Not applicable. Competing interests The authors declare no competing interests. Footnotes Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Wanmeng Wang and Jiahao Yun contributed equally to this work. Contributor Information Bo Chen, Email: [email protected]. Hong Bai, Email: [email protected]. Ying Li, Email: [email protected]. References 1. 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Supplementary Materials Supplementary Material 1 (1,017KB, mp4) Supplementary Material 2 (39.1MB, docx) Data Availability Statement The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. 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