IntroductionDespite advances in biomaterials and surgical techniques, implant-associated infections (IAIs) continue to jeopardize the success of bone defect repair, often culminating in implant failure and adverse patient outcomes.1,2 The systematic use of antibiotics or implant replacement surgery may be an effective clinical option to address this issue.3 However, limited drug targeting and bacterial drug resistance may compromise antibacterial efficacy. Additionally, both the abundant release of endotoxins following bacterial death triggers excessive inflammation,4 and the induction of osteoclasts by the bacterial microenvironment restricts the repair of bones.5 Consequently, the development of nonantibiotic coatings that can provide effective antimicrobial, anti-inflammatory, and osseointegration therapies is highly important for combating IAIs.Sonodynamic therapy (SDT) represents an emerging antibacterial strategy leverages ultrasound to induce sonosensitizer activation, which enables localized generation of reactive oxygen species (ROS).6,7,8 ROS exhibit broad-spectrum bactericidal effects by inflicting oxidative stress on vital biomolecules, including proteins, membrane lipids, and nucleic acids.9,10,11 Despite its therapeutic potential, SDT efficacy is fundamentally limited by the transient nature and poor diffusivity of ROS, exacerbated by local hypoxia.12,13,14 Consequently, various approaches have been explored to optimize SDT efficacy, including enhancing the bacterial targeting of sonosensitizers,15,16 alleviating hypoxia,17 and integrating metabolic therapies.18 Meanwhile, excessive accumulation of ROS may exacerbate inflammation and induce cellular dysfunction, thereby impeding wound healing.19 Therefore, rational regulation of redox homeostasis is equally crucial. Elucidating the mechanisms underlying bacterial death is pivotal to the rational design of antimicrobial materials. Many studies have demonstrated that ROS kill bacteria through multiple pathways. Emerging evidence suggests that bacterial death often results from the synergy of several mechanisms, including metal ion-induced metabolic disruption.20 Therefore, systematically identifying and elucidating these diverse bacterial death pathways not only facilitates a comprehensive evaluation of the antibacterial performance of materials, but also reveals potential synergistic or compensatory mechanisms, thereby offering theoretical guidance for functional optimization.Curcumin (Cur), a naturally derived polyphenolic sonosensitizer, has been widely utilized in SDT due to its broad-spectrum antibacterial and antitumor activities, as well as its excellent biosafety profile.21 However, free Cur faces significant clinical limitations due to its inadequate aqueous solubility, poor stability in physiological environments, and restricted bioavailability.22,23 Notably, the β-diketone group within the Cur molecule possesses a high degree of conjugation, enabling it to coordinate stably with various metal ions (e.g., Fe(II), Cu(II), Zn(II), Cu(I)), thus enhancing its bioavailability.24,25 In addition, Cur–CuS complexes have shown excellent sonosensitizing efficacy against Staphylococcus aureus infections.26 Despite the limitations of free Cur, its strong metal-coordination ability makes it highly promising for the development of composite systems with enhanced ultrasound responsiveness. To this end, bioheterojunctions (bio-HJs) which are constructed by combining two semiconductors with distinct bandgaps, have emerged as effective nanoreactors for enhancing SDT. Upon ultrasound irradiation, the interfacial electron transfer between components within the bio-HJs markedly promotes the generation of ROS.9,27 Given Cur inherent properties and its strong affinity for metal ions, it represents an ideal candidate for interface engineering in bio-HJ design, thereby further increasing ROS production and improving sonodynamic efficacy. In addition, Cur excellent antioxidant and anti-inflammatory properties have garnered increasing interest.28,29 It can exert antioxidant effects by eliminating ROS through electron transfer or hydrogen-donation mechanisms30 and modulate inflammation by targeting relevant signaling molecules, thereby downregulating pro-inflammatory cytokines such as TNF-α, IL-1, and IL-6.31 Recent studies have demonstrated that Cur-based functional materials can alleviate oxidative stress and inflammatory responses, facilitate granulation tissue formation and angiogenesis, and thereby accelerate wound healing.32Cuprous oxide (Cu2O) nanoparticles, as representative p-type semiconductors, exhibit distinctive optical, electronic, and catalytic properties and have been extensively explored for their antibacterial applications.33,34 Cu2O has diverse structural morphologies; notably, its shell-in-shell structure35 may enable sequential antibacterial action and tissue regeneration by leveraging distinct functionalities of each shell layer. Excess intracellular copper disturbs mitochondrial homeostasis by promoting the misfolding and accumulation of lipoylated enzymes, particularly dihydrolipoamide S-acetyltransferase (DLAT), and disrupting iron–sulfur cluster–dependent metabolic pathways in the tricarboxylic acid cycle.36,37,38 This process induces profound proteotoxic stress that results in tumor cell death, which offers new perspectives on copper-mediated bacterial death.39 Therefore, SDT in conjunction with metabolic disruption therapy for bacterial copper overload can achieve highly effective and sustained antibacterial action. In addition, the released Cu(I) can undergo disproportionation reactions with hydrogen peroxide in an acidic environment to produce Cu(II),40 which subsequently engages in a self-catalysis-induced chelation reaction to form Cu(II)-Cur. Cu(II)-Cur complexes can enhance antioxidant efficacy, induce M2 macrophage polarization, and alleviate inflammation.41 Based on these mechanisms, we designed and fabricated a multifunctional shell-in-shell copper-based coating. The outer shell incorporates a Cur/Cu2O heterojunction to facilitate efficient sonodynamic antibacterial activity and disrupt bacterial metabolism, whereas the inner shell is doped with strontium to promote bone tissue regeneration. This multilayered architecture exerts sequential and synergistic effects across antibacterial, antioxidative, and osteogenic processes, holding great promise for overcoming current bottlenecks in the treatment of IAIs (Fig. 1).Fig. 1Schematic of the synthesis and IAI Treatment. a Schematic of the synthetic of Pp-bioHJs. b Schematic depicting the antibacterial strategy of Pp-bioHJs for IAI therapy. The treatment enhances bacterial killing by ultrasound-triggered ROS generation from HB-bioHJs and intracellular Cu(I) overload–induced cuproptosis-like death. The bone scaffold exhibited anti-inflammation, immunoregulation, and osteogenic via Cu(II)-Cur-activated self-catalysis regulation and Sr-mediated treatment in an infected bone implant modelFull size imageResultsSynthesis and characterizationCu2O-Sr/Cur was prepared via a one-pot hydrothermal synthesis, with a schematic diagram of the product presented in Supplementary Fig. 1. Briefly, polyvinyl pyrrolidone powder was added to CuSO4·5H2O and SrCl2 solutions, which were reduced by N2H4·H2O to yield single-shell Cu2O-Sr (Supplementary Fig. 2a, b). N2H4·H2O was added once again to form an additional nanoshell around the structure of the Cu2O-Sr single-shell nanoshell. Cur was subsequently introduced alongside the shell-in-shell Cu2O-Sr nanoshell into a DMF solution, followed by thorough stirring and vacuum drying to obtain the desired Cu2O-Sr/Cur composite. Without the addition of Cur, the shell-in-shell Cu2O-Sr nanoshell possessed a microspherical structure with a rough surface and an average size of 500 nm (Fig. 2a, b). Transmission electron microscopy (TEM) revealed shell-in-shell nanostructures (Fig. 2c). Scanning electron microscopy (SEM) revealed a uniform distribution of Cu-Cur nanodots on the surface of the double-layered Cu2O nanospheres (Fig. 2d, e), and the TEM image of the Cu2O-Sr/Cur microspheres confirmed the same result (Fig. 2f). The high-resolution TEM (HRTEM) image revealed a compact interface between the Cur nanodots and the Cu2O-Sr nanospheres (Fig. 2g). High-resolution lattice fringes measuring 0.244 nm corresponded to the (111) planes of Cu2O, while the 0.260 nm spacing matched that of Cur crystals. The Fourier transform infrared spectroscopy (FTIR) analysis of the Cu2O-Sr/Cur composites displayed characteristic Cur absorption bands that exhibited a e redshift compared to pure Cur powder (Fig. 2i). The observed redshift likely results from hydrogen bonding or metal–ligand coordination between Cur and the Cu2O substrate, which weakens the functional group bond energy and decreases their vibrational frequency. The uniform distributions of C, Cu, O and Sr on the spherical structure, as confirmed by EDS (Fig. 2h, Supplementary Fig. 2c), further validated the successful chelation of Cur. EDS analysis of Cu2O-Sr/Cur further revealed that Sr is predominantly localized within the inner shell. The Sr release experiment further confirmed that the coating materials on the scaffold maintained good adhesion stability under US conditions. The rapid accumulation of Sr between days 7 and 14 was attributed to the decomposition of the inner Sr-containing layer, triggered by the acid-induced degradation of the Cu2O shell structure. (Supplementary Fig. 2d). The XRD pattern of Cu2O-Sr/Cur revealed characteristic peaks of Cu2O and Cur, which was consistent with the SAED results and confirmed the success of the material synthesis (Fig. 2j). While the characteristic peaks of Cu2O are clearly observed, the signals from Cur appear relatively weak. This can be attributed to the low content and uniform distribution of Cur in the composite.Fig. 2Characterization of nanoparticles. a, b, d, e SEM images of shell-in-shell Cu2O-Sr (a, b) and Cu2O-Sr/Cur (d, e). c, f TEM images of shell-in-shell Cu2O-Sr (c) and Cu2O-Sr/Cur (f). g HRTEM image of Cu2O-Sr/Cur. h EDS images showing the elemental composition of Cu2O-Sr/Cur. i FTIR spectra of Cur and Cu2O-Sr/Cur. j XRD patterns of Cu2O-Sr/Cur. k XPS spectra comparing surface chemical states across various samplesFull size imagePolydopamine (pDA) enables strong adhesion via metal coordination and π–π interactions and was employed to immobilize Cu2O-Sr/Cur onto the PEKK scaffold.42,43 SEM and X-ray photoelectron spectroscopy (XPS) confirmed the successful construction of PEKK-pDA-Cu2O-Sr/Cur (Pp-CSC), which was identified by two clear peaks for C 1 s and O 1 s (Supplementary Fig. 2e, Fig. 2K). Supplementary Fig. 2f displays the Cu 2p XPS spectrum, featuring characteristic peaks near 932 and 952 eV, indicative of Cu(I) and Cu(II) species. To evaluate the response to ultrasonic treatment, we examined the stability of the Cu2O-Sr/Cur layer deposited on the PEKK surface (Supplementary Fig. 3). In Process A, the scaffolds released both Cu and Cu2O-Sr/Cur particles, whereas in Process B, only Cu was released. ICP analysis revealed that the Cu concentrations obtained via both procedures were similar and did not significantly differ from those obtained without the US control group, indicating that the Cu2O-Sr/Cur on the PEKK substrate remained stable due to the strong binding properties of pDA.Sono-electric and sono-catalytic performanceAs shown in Fig. 3a, after US irradiation, Cu2O-Sr/Cur exhibited a significant sonocurrent density, whereas the other groups exhibited only minor fluctuations. These results indicate that the herbal bioheterojunctions (HB-bioHJs) formed by Cu2O-Sr/Cur improved electron‒hole separation and facilitated efficient charge transfer at the interface. In addition, electrochemical impedance spectroscopy (EIS) revealed a decreased interface resistance in Cu2O-Sr/Cur, indicating that the transfer of the sonocarrier could decrease the charge transfer barrier and facilitate charge transfer (Fig. 3b).Fig. 3SDT-mediated sonocatalytic capability and DFT calculations of interfacial Engineering. a Sonocurrent response of different synthesized materials (200 μg mL−1) under US. b EIS of different synthesized materials (200 μg mL−1) under US. c, d1O2 (c) and •OH (d) obtained from the ESR of Cu2O-Sr/Cur (200 μg mL−1) for various times under US. e Energy band structure of Cu2O and Cur pre- and post-interaction. f Cu2O–Cur adsorption configuration. g Differential charge density map at the Cu2O–Cur interface (blue: electron loss; yellow: electron gain). h DOS spectra of Cu2O–Cur interfaceFull size imageTo assess the sonocatalytic enhancement of Cu2O-Sr/Cur HB-bioHJs, singlet oxygen (1O2) and hydroxyl radicals (•OH) generated under US irradiation were quantified via 1,3-diphenylisobenzofuran (DPBF) and methylene blue (MB) probes. Prolonged ultrasonic irradiation and higher Cu2O-Sr/Cur concentrations led to a marked reduction in DPBF absorbance, which indicated effective 1O2 generation (Supplementary Fig. 4a, b). A pronounced decline in MB content was detected following Cu2O-Sr/Cur-mediated ultrasonic activation, with both concentration- and time-dependent degradation profiles, which further confirms the efficient generation of •OH. (Supplementary Fig. 4d, e). This performance was notably superior to that of the samples treated with Cu2O-Sr (Supplementary Fig. 4c, f). Considering the interference of Cur on the absorbance after dissolution, electron spin resonance (ESR) spectroscopy was applied to evaluate and contrast the ROS production efficiency between Cur and Cu2O-Sr/Cur. The results revealed that Cu2O-Sr/Cur generated significantly higher levels of ROS than Cur did under identical conditions (Fig. 3c, d, Supplementary Fig. 5a–d). These findings underscore the superior sonodynamic performance of Cu2O-Sr/Cur, highlighting its promising potential as a sonosensitizer for antibacterial applications.Catalytic mechanism and density function theory calculationsThe ultraviolet-visible diffuse reflection spectroscopy (UV‒vis DRS) results for the synthesized materials are presented in Supplementary Fig. 6a. The optical gaps of Cur, Cu2O-Sr, and Cu2O-Sr/Cur were calculated as 2.148 eV, 1.758 eV, and 1.284 eV, respectively (Supplementary Fig. 6b, c). The valence bands (VBs) of Cu2O-Sr and Cu2O-Sr/Cur, along with the highest unoccupied molecular orbital (HOMO) of Cur derived from the XPS valence band spectrum, were determined to be 0.896 eV, 1.077 eV and 0.431 eV, respectively (Supplementary Fig. 6d, e). When forming a tight interface, Cu2O-Sr/Cur exhibited a low optical gap (Fig. 3e). Therefore, US could activate Cu2O-Sr/Cur, increase the utilization of electrons, and further improve its redox capability, resulting in the production of more ROS.Calculations via Density Functional Theory (DFT) focused on the (111) surfaces of Cu2O and Cur were performed to to simulate interfacial carrier transport and elucidate their electronic interactions. As shown in Fig. 3f, the crystal structures of Cu2O and Cur were modeled, revealing an adsorption energy of −2.26 eV, which suggests a thermodynamically favorable interaction at the interface. The differential charge density (DCD) after bonding revealed a pronounced electron enrichment on the Cu2O surface and marked decrease on the Cur side, supporting the presence of an internal electric field (Fig. 3g). In addition, we measured the distance between the atoms. In the clear charge transfer regions (marked by circles in Supplementary Fig. 7), after the formation of a tight interface between Cur and Cu2O, the bond length and bond angle of Cu•••O changed dramatically compared with the corresponding values before contact (Supplementary Table 1). To verify the above speculation, we measured the distance between related atoms (Supplementary Table 2). On the basis of the reported van der Waals radii of H (1.20 Å), O (1.52 Å), and Cu (1.40 Å) atoms, the total van der Waals radii of H•••O and O•••Cu were calculated to be 2.72 and 2.92 Å, respectively. The bond lengths of H•••O and O•••Cu were shorter than the sum of their van der Waals radii, indicating van der Waals interactions. Figure 3h illustrates the density of states (DOS) characteristics at the intimate Cu2O–Cur interface. The analysis indicates that electronic states near the Fermi level (EF = 0 eV) are predominantly contributed by Cu2O. The observed enhancement in DOS intensity relative to pristine Cu2O suggests improved electrical conductivity resulting from interaction with Cur.Antimicrobial activity in vitroCur, Cu2O-Sr, and Cu2O-Sr/Cur were immobilized onto PEKK scaffolds via pDA and designated Pp-C, Pp-CS, and Pp-CSC, respectively. Under US stimulation, the viability of Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) decreased negligibly following treatment with PEKK-pDA (Pp). However, Pp-CSC achieved 99.56% antibacterial efficiency against S. aureus and 99.43% antibacterial efficiency against E. coli under US, suggesting its potential as an antibiotic alternative. Without US, both Pp-CS and Pp-CSC exhibited certain antibacterial activities (Fig. 4a, b, Supplementary Fig. 8). Additionally, LIVE/DEAD fluorescence confirmed the same results mentioned above. (Fig. 4e). To verify the antibacterial effect triggered by SDT, ROS levels were assessed via the fluorescent probe 2′,7′-dichlorofluorescein diacetate (DCFH-DA). Upon US activation, the Pp-CSC group exhibited a nearly fourfold increase in fluorescence compared with baseline, significantly surpassing all other groups, suggesting its superior ROS generating capability (Fig. 4c, d).Fig. 4Antibacterial performance in vitro. a, b Quantification of S. aureus (a) and E. coli (b) following various treatments. c Quantification of the fluorescence area via DCFH. d The fluorescence image of intracellular ROS via DCFH-DA (green) of S. aureus after treatment with different scaffolds. e Live/dead CLSM of biofilms on scaffolds ±US (f) SEM of S. aureus and E. coli incubated with different scaffolds. g TEM of of S. aureus and E. coli. Violet arrows: plasmolysis; red stars: reduced organelles. Statistical significance among biologically independent samples (n = 3) was determined via ANOVA followed by Tukey’s multiple comparisons tests. The data are presented as means ± SDs. Significant differences between groups are indicated as *p