A biomimetic cascade nanoplatform that integrates a photothermal nanozyme core, surface-anchored DNase I-functionalized gold nanoclusters, and a pre-activated macrophage membrane camouflage enables synergistic biofilm eradication and immune microenvironment modulation against drug-resistant infections.
Abstract
Methicillin-resistant Staphylococcus aureus (MRSA) biofilm-associated infections remain a formidable clinical challenge, owing to limited antibiotic penetration, an immunosuppressive microenvironment, and recurrent biofilm regeneration. Effective long-term immunomodulatory strategies to prevent reinfection are still lacking. To address this issue, we have constructed a biomimetic cascade nanoplatform (MACP@DG@CM) that integrates a photothermal nanozyme core, surface-anchored DNase I-functionalized gold nanoclusters (DNase I-GNCs), and a pre-activated macrophage membrane camouflage. This design enables synergistic biofilm eradication and immune microenvironment modulation. Under an 808 nm near-infrared (NIR) irradiation, the nanoplatform triggers a cascade radical storm, including photothermal hyperthermia, a peroxidase-like hydroxyl radical (·OH) burst, nitric oxide (NO) release, and DNase I-mediated extracellular DNA (eDNA) degradation. Concurrently, it depletes glutathione (GSH), disrupts bacterial redox homeostasis, and causes severe membrane damage. Transcriptomic analysis reveals that the nanoplatform perturbs bacterial two-component systems, d-amino acid metabolism, and antimicrobial peptide resistance pathways. Enzyme-linked immunosorbent assay (ELISA) further confirms up-regulated pro-inflammatory cytokines and down-regulated anti-inflammatory cytokines, indicating an activated inflammatory response. In an MRSA-infected wound model, it accelerates wound closure, promotes collagen deposition, and modulates inflammation. Collectively, this biomimetic cascade nanoplatform provides a synergistic strategy for biofilm eradication and immune activation against drug-resistant infections.
Methicillin-resistant Staphylococcus aureus (MRSA)-induced pneumonia remains clinically challenging because antibiotic monotherapy is often insufficient to eradicate bacteria at pulmonary lesions and fails to resolve infection-amplified oxidative and inflammatory injury. Herein, we report a neutrophil membrane-cloaked, melanin-biomineralized MnO2 nanozyme platform co-loaded with curcumin and vancomycin (VC@NMM) for targeted antibacterial and immunoregulatory therapy of MRSA pneumonia. Through melanin-mediated biomineralization with KMnO4, a biocompatible MnO2 nanozyme framework is constructed with abundant interfacial sites for dual-drug loading and catalytic microenvironment regulation. In this integrated system, vancomycin directly inhibits MRSA growth, curcumin potentiates antibacterial activity and attenuates oxidative inflammation, and the MnO2 nanozyme mediates ROS scavenging, H2O2 decomposition, oxygenation improvement, and bacterial disruption. Neutrophil membrane cloaking further confers prolonged circulation and inflammation-tropic accumulation at MRSA-colonized lung tissues. Consequently, VC@NMM effectively reduces the required vancomycin dosage, disrupts bacterial integrity, induces protein leakage, impairs ATP metabolism, and suppresses MRSA survival in vitro. In MRSA pneumonia mouse model, VC@NMM significantly reduces pulmonary bacterial burden, alleviates edema and histopathological injury, inhibits ROS/NF-κB inflammatory signaling, remodels macrophage polarization, and prolongs survival. Collectively, this work establishes a biomineralized biomimetic nanozyme strategy that couples targeted antibiotic delivery with catalytic microenvironment remodeling and inflammation resolution for effective bacterial pneumonia therapy.
Hening Liu, Yue Yin, Ziwei Yan et al.· Journal of Controlled Releas...· 0 citations
Methicillin-resistant Staphylococcus aureus (MRSA) infections represent a severe global clinical threat due to its multi-antibiotic resistance, abundant virulence factors, and complex pathogenic mechanisms. In the present study, hollow copper sulfide (CuS) nanoparticles (NPs) with a strong photothermal effect were employed as carriers for the loading of the NO-releasing bioactive molecule S-nitrosoglycine (GSNO). These NPs were also camouflaged with mouse red blood cell membranes (RBCMs) via extrusion to fabricate CuS-GSNO@RBCM NPs designed to effectively eliminate MRSA and its biofilms. Under 1064 nm near-infrared laser irradiation, CuS NPs had a mild photothermal effect, establishing an in situ catalytic platform that boosted reactive oxygen species (ROS) production. In the acidic infectious microenvironment, the release of copper ions induced GSNO to produce NO for reactive nitrogen species (RNS) generation. The ROS and RNS generated in situ by this system consumed endogenous MRSA glutathione, disrupting redox homeostasis, with the additional presence of copper ion-mediated copper death forming a multi-bactericidal network. The RBCMs also neutralized proteins secreted by MRSA to reduce lung cell injury. In vitro and in vivo experiments were employed to verify the MRSA-elimination efficacy of the proposed system, which offers an innovative nanotherapeutic strategy for the precise treatment of drug-resistant bacterial infections.
Xiangjun Chen, Sai Zhang, Yating Liu et al.· Small· 0 citations
Current clinical management of periodontitis, a chronic inflammatory disease driven by dysbiotic biofilms, faces a persistent challenge: biofilm-associated infections remain difficult to eradicate owing to the resilient energy metabolism and high virulence of key pathogens such as Porphyromonas gingivalis. To address this challenge, we developed ultrasmall AHMP-stabilized gold nanoclusters (AHMP@AuNCs) based on a bioenergetics-centered "Metabolic Trap" paradigm. Their sub-2-nm architecture supports bacterial-interior access, while preferential bacterial accumulation may be facilitated by the pyrimidine-mimetic ligand environment, potentially through pyrimidine-associated recognition or uptake processes. A proton-responsive Au-ligand interface undergoes reversible electronic-state modulation, with near-neutral to weakly alkaline intracellular conditions favoring a charge-transfer-associated state. Following bacterial accumulation, AHMP@AuNCs disrupt proton homeostasis and energetic coupling, leading to ATP and NAD depletion, nucleotide metabolic imbalance, secondary oxidative stress, and suppression of T9SS-dependent virulence. Integrated metabolomic and transcriptomic analyses reveal coordinated rewiring of energy, nucleotide, and virulence networks, supporting the "Metabolic Trap" concept. Across oral biofilm models, AHMP@AuNCs inhibit biofilm formation and access internal regions of mature biofilms, disrupting established architecture while showing limited cytotoxicity in the evaluated host-cell models. In experimental periodontitis, local administration preserved epithelial barrier integrity, attenuated inflammation, reduced the P. gingivalis-associated burden, and limited periodontal tissue destruction, with favorable short-term tolerability. This strategy demonstrates that targeting intracellular energy vulnerabilities can achieve antibacterial, antibiofilm, and antivirulence effects against persistent infections.
ABSTRACT Biofilms, a major cause of chronic bacterial infections, present significant treatment challenges due to their protective extracellular matrix that shields bacteria from both antibiotics and host immune defenses. To treat biofilms more effectively, here we discovered a biofilm‐binding peptide from a phage library and verified that it selectively bound the polysaccharides on the biofilm. We then engineered M13 phage into trifunctional nanofibers displaying the biofilm‐binding peptide at the tip and carrying gold nanoparticles (AuNPs, as photothermal agents) and tetrakis(4‐carboxyphenyl) porphyrin (TCPP, as a photosensitizer) on the sidewall for combined phototherapy. This design enhances binding/anchoring and eradication of biofilms by leveraging the unique properties of each component. The phage nanofibers efficiently bound biofilms and promoted the transfer of heat and penetration of reactive oxygen species (ROS) into the biofilm, leading to cell death. Therefore, under light irradiation, the engineered phage nanofibers effectively eradicated the biofilms by AuNP‐induced photothermal therapy (PTT) and TCPP‐assisted photodynamic therapy (PDT) in a biofilm‐associated skin wound model. Transcriptomic profiling suggests stress‐response signatures consistent with oxidative/thermal injury. This study presents a promising ternary synergistic strategy for eradicating biofilms, potentially improving clinical outcomes in wound infection management.
Ying Cao, Tao Yang, Rui Wang et al.· Advancement of science· 0 citations
A dual-functional nanoplatform constructed through the coordination-driven assembly of gallium ions (Ga3+) and polydopamine (PDA) for synergistic photothermal and metabolic antibiofilm therapy provides a promising therapeutic strategy for the management of biofilm-associated infections.
Xinyan Zheng, Jie Chen, Tongtong Yin et al.· Biomacromolecules· 0 citations
The inherent limitations of conventional nanozymes, particularly their suboptimal catalytic activity, severely restrict their efficacy against resilient bacterial biofilms. In response, an Au-Bi bimetallic nanozyme-based sonosensitizer (Bi2O3@AuBi-arg/4-MPBA, BABa4), which harnesses ultrasound (US) to power a multi-modal antibacterial strategy, is engineered. The platform is constructed by loading the NO donor L-arginine (L-arg) onto a mesoporous Bi2O3@AuBi (BAB) bimetallic nanozyme and modifying its surface with a bacterial-targeting ligand 4-mercaptophenylboronic acid (4-MPBA). Under US irradiation, Bi2O3 acts as an efficient sonosensitizer, generating electron-hole pairs, which not only produce singlet oxygen but also transfer to the AuBi nanozyme, markedly enhancing its POD-like activity and creating a synergistic ROS storm. Concurrently, the US-triggered release of nitric oxide from L-arg degrades the extracellular polymeric substance (EPS) of biofilms by regulating cyclic dimeric guanosine monophosphate (c-di-GMP) levels. This multifaceted approach, combining sonodynamic therapy, US-enhanced nanozyme catalysis, and NO-mediated biofilm dispersion, demonstrates potent antibacterial activity and promotes effective wound healing, presenting a robust strategy for combating resistant bacterial infections.
Ruilin Lou, Zhifang Wang, Yaqi Cui et al.· Small· 0 citations
