On-demand celastrol delivery by hyaluronic acid-porphyrinic metal-organic frameworks for synergistic sonodynamic/pharmacological antibacterial therapy.

Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most prevalent bacterial pathogens. The multi-drug resistance and strong biofilm-forming ability make the treatment of MRSA infections challenging. It is urgent to develop antibiotic-free, noninvasive and effective strategies against MRSA infections. Recently, celastrol (CLT), a natural phytochemical, showed potent antimicrobial activity against planktonic MRSA. However, its further development was hindered by low solubility, short plasma half-life, poor bioavailability and severe systemic toxicity. To address these issues, hyaluronic acid-porphyrinic metal-organic frameworks loaded with CLT (HA@PCN-CLT) were fabricated for combating MRSA biofilms. Once encountering the overexpressed HAases in biofilm, their surface charge reversed to positive to facilitate biofilm penetration under ultrasound irradiation, which was revealed by 3D fluorescence image. In vitro release profiles suggested that HA@PCNCLT exhibited ultrasound promoted pH/HAase-responsive release properties. Taking advantage of superior sonodynamic performance and on-demand CLT release, HA@PCN-CLT NPs effectively reduced biofilm biomass and killed planktonic and biofilm-embedded MRSA. Moreover, HA@PCN-CLT NPs completely eradicated the MRSA infection in mice under ultrasound irradiation and promoted abscess healing by stimulating angiogenesis and collagen deposition, accompanied by excellent biocompatibility and negligible toxicity in vivo. HA@PCN-CLT NPs provided a promising antibiotic-free strategy against MRSA biofilms through synergistic combination of sonodynamic therapy and phytochemicals.