Dual-membrane bioinspired nanocarriers for targeted therapy of MRSA-induced acute lung injury and bacteremia

Bioinspired nanoparticles enhance the targeting of specific organs by facilitating interactions and communication at the nano-bio interface. Combining human neutrophil and lung epithelial cell membranes for nanoparticle cloaking offers distinct advantages in binding to bacteria and pulmonary epithelium, thus targeting infection-induced inflammatory areas. This study aimed to develop rifampicin-loaded biomimetic nanocarriers by wrapping a polymeric core with dual membranes derived from neutrophils and A549 cells, inheriting the membrane characteristics of the native cells. To evaluate the therapeutic efficacy of these nanocarriers, methicillin-resistant <i>Staphylococcus aureus</i> (MRSA)-induced acute lung injury (ALI) and bacteremia models were established in mice. The hybrid membrane-coated nanoparticles exhibited an average diameter of 191 nm and a nearly neutral surface charge of -2.7 mV. Zeta potential measurements, gel electrophoresis, and scanning electron microscopy (SEM) confirmed the successful decoration of the membranes on the nanoparticles. The dual membrane-coated nanoparticles were readily and rapidly ingested by lung epithelial cells within five minutes, demonstrating superior cellular uptake compared to those coated with a single membrane. SEM analysis showed significant adherence of the hybrid membrane-coated nanoparticles to the MRSA surface. The rifampicin-loaded nanocarriers effectively eradicated MRSA in its planktonic, biofilm, and intracellular forms. <i>In vivo</i> biodistribution studies in ALI mice revealed that the hybrid membrane-coated nanoparticles effectively targeted inflamed lungs, showing a two-fold increase in lung accumulation compared to the unfunctionalized nanoparticles. This targeted delivery significantly reduced the severity of lung damage caused by ALI and bacteremia, including MRSA burden, cytokine/chemokine expression, alveolar edema, and immune cell infiltration. The bioinspired nanocarriers improved the pulmonary targeting of inflamed sites and neutralized the proinflammatory mediators and toxins in the injured lung. No significant toxicity was observed in the healthy mice receiving the nanocarriers. Thus, targeted biomimetic nanocarriers, utilizing antibacterial and anti-inflammatory strategies, show promising benefits for treating pulmonary injury.