Bone-targeting ZIF-8 based nanoparticles loaded with vancomycin for the treatment of MRSA-induced periprosthetic joint infection

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.