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Bone-targeting ZIF-8 based nanoparticles loaded with vancomycin for the treatment of MRSA-induced periprosthetic
Shuailong Liang1, Yixiao Pan2, Jiahao Wang3
1Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, China; Hunan Engineering Research Center of Biomedical Metal and Ceramic Implants, Xiangya Hospital, Central South University, Changsha, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.
Abstract:
Periprosthetic joint infection (PJI) caused by methicillin-resistant Staphylococcus aureus (MRSA) has become a global healthcare burden owing to increased drug resistance. The effectiveness of traditional antimicrobial drugs in their treatments is becoming increasingly limited. The search for new drug delivery strategies may help to address this issue. In this study, we fabricated vancomycin (Van)-loaded and zoledronic acid (ZOL)-modified zeolitic imidazolate framework-8 (ZIF-8) nanoparticles (NPs), named VZZ-8 NPs, which could effectively treat MRSA-induced PJI. ZOL endowed VZZ-8 NPs with preferential bone-targeting capability, particularly accumulating at sites of elevated bone metabolism during injury/infection, thereby ensuring maximized therapeutic bioavailability in vivo. VZZ-8 NPs maintained ZIF-8-mimetic stability at physiological pH (7.4) yet rapidly degraded in acidic infection microenvironments (pH 5.0), enabling on-demand co-release of Zn2+ and Van for synergistic antibacterial effects. Moreover, Zn2+ released from VZZ-8 NPs disrupted bacterial membrane permeability, thereby potentiating Van antimicrobial activity and reducing the required therapeutic dosage of Van. In vitro studies demonstrated that VZZ-8 NPs effectively eradicated 93.84 ± 7.38 % of MRSA and inhibited biofilm formation by 95.36 ± 0.13 %. In a murine model of MRSA-induced PJI, VZZ-8 NPs displayed robust antibacterial efficacy while simultaneously suppressing local TNF-α and IL-6 expression and preventing infection-mediated osteolysis, demonstrating comprehensive therapeutic potential for PJI treatment. Consequently, the engineered VZZ-8 NPs developed in this study provide an effective therapeutic approach for MRSA-induced PJI through their dual capability of targeted delivery and pH-responsive drug release.
Insights
New nanoparticles loaded with vancomycin and zoledronic acid effectively treat methicillin-resistant Staphylococcus aureus periprosthetic joint infection. This targeted, pH-responsive drug delivery system shows significant antibacterial activity and reduces infection-related bone damage.
Area of Science:
- Biomaterials Science
- Nanotechnology
- Infectious Diseases
Background:
- Periprosthetic joint infection (PJI) caused by methicillin-resistant Staphylococcus aureus (MRSA) presents a significant global health challenge due to increasing antimicrobial resistance.
- The efficacy of conventional antibiotics for MRSA-PJI is diminishing, necessitating novel therapeutic strategies and drug delivery systems.
Purpose of the Study:
- To develop and evaluate vancomycin (Van)-loaded and zoledronic acid (ZOL)-modified zeolitic imidazolate framework-8 (ZIF-8) nanoparticles (VZZ-8 NPs) for targeted treatment of MRSA-induced PJI.
- To investigate the bone-targeting capability, pH-responsive drug release, synergistic antibacterial effects, and therapeutic efficacy of VZZ-8 NPs in vitro and in vivo.
Main Methods:
- Fabrication of ZIF-8 nanoparticles co-loaded with vancomycin and modified with zoledronic acid (VZZ-8 NPs).
- Assessment of VZZ-8 NPs' stability, pH-responsive degradation, and drug release kinetics at physiological and acidic pH.
- In vitro evaluation of antibacterial activity against MRSA and inhibition of biofilm formation.
- In vivo studies using a murine model of MRSA-induced PJI to assess therapeutic efficacy, anti-inflammatory effects, and prevention of osteolysis.
Main Results:
- VZZ-8 NPs demonstrated preferential bone targeting due to ZOL modification, accumulating at infection sites.
- Rapid degradation of VZZ-8 NPs in acidic microenvironments (pH 5.0) triggered on-demand co-release of Zn²⁺ and Van.
- Synergistic antibacterial action of Zn²⁺ and Van significantly enhanced MRSA eradication (93.84 ± 7.38%) and inhibited biofilm formation (95.36 ± 0.13%).
- In vivo, VZZ-8 NPs effectively treated MRSA-PJI, suppressed local inflammatory markers (TNF-α, IL-6), and prevented osteolysis.
Conclusions:
- Engineered VZZ-8 NPs offer a promising therapeutic strategy for MRSA-PJI, combining targeted delivery and pH-responsive release for enhanced efficacy.
- The dual action of targeted delivery and synergistic drug release from VZZ-8 NPs provides a comprehensive approach to combatting MRSA-induced bone infections.
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