Targeted Delivery of Peptide Nucleic Acid by Biomimetic Nanoparticles based on Extracellular Vesicle-coated Mesoporous Silica Nanoparticles

Background: Peptide nucleic acid (PNA) plays an important role in antimicrobial activity, but its cellular permeability is poor. To overcome this limitation, we constructed biomimetic nanoparticles by using extracellular vesicle (EV)-coated mesoporous silicon nanoparticles (MSNs) to deliver PNA to Staphylococcus aureus (S. aureus) and improve its antisense therapeutic effect. Methods: MSN was prepared by the sol-gel method, and EV was extracted by affinity resin chromatography. EV was coated on MSN by simple sonication (50 W, 3 mins) to prepare biomimetic nanoparticles with PNA-loaded MSN as the core and EV isolated from S. aureus as the shell. Results: The MSN prepared by the sol-gel method had a uniform particle size (100 nm) and well-defined pore size for loading PNA with good encapsulation efficiency (62.92%) and drug loading (7.74%). The concentration of EV extracted by affinity resin chromatography was about 1.74 mg/mL. EV could be well coated on MSN through simple ultrasonic treatment (50 W, 3 mins), and the stability and blood compatibility of MSN@ EV were good. Internalization experiments showed that EV could selectively enhance the uptake of biomimetic nanoparticles by S. aureus. Preliminary in vitro antibacterial tests revealed that PNA@MSN@EV exhibited enhanced antibacterial activity against S. aureus and had stronger bactericidal activity than free PNA and PNA@MSN at equivalent PNA concentrations (8 μM). Conclusion: Biomimetic nanoparticles based on EV-coated MSN offer a new strategy to improve the efficacy of PNA for the treatment of bacterial infections, and the technology holds promise for extension to the delivery of antibiotics that are traditionally minimally effective or prone to resistance.