Macrophage-membrane-camouflaged nanoagents for precise bacterial clearance

Bacterial infections remain a significant public health threat. While antibiotics have mitigated their impact, overuse and misuse have driven the emergence of drug-resistant bacteria, compromising treatment outcomes. Additionally, bacterial biofilms have further diminished the effectiveness of current antibiotics, underscoring the urgent need for new antibacterial therapies. Recent advancements in antibacterial nanoagents, show promise due to their unique physical and chemical properties. These nanoagents have been approved by the US Food and Drug Administration. However, challenges such as protein coating in vivo, rapid immune clearance, and difficulty in targeting deep-seated infections (e.g., pneumonia, meningitis, and implant-related infections) limit their clinical application. In these locations, bacteria release toxins, proliferate within phagocytes, and evade immune attacks, highlighting the need for novel therapeutic strategies to target bacteria hidden in deep tissues or within host cells.

Macrophages play a pivotal role in innate immunity, performing roles in phagocytosis, antigen presentation, and immune modulation. They inherently recognize and eliminate pathogens through pattern recognition receptors such as Toll-like receptors. Additionally, they exhibit a natural affinity for inflammatory sites, guided by adhesion molecules, such as integrins and selectins, and chemokine receptors, such as CCR2, which enable their migration across endothelial barriers. They may also infiltrate the blood-brain barrier. The ability of macrophages to target inflammation and internalize proinflammatory agents such as lipopolysaccharide (LPS) makes them promising for drug delivery, immunotherapy, and treating inflammatory and infectious diseases. Their selective targeting and strong barrier penetration enhance their potential as versatile therapeutic vehicles for direct delivery to infection and inflammation sites. Researchers have leveraged these properties to coat nanoagents with extracted macrophage membranes, forming core-shell nanostructures that enhance immune evasion and targeted drug delivery. Common macrophage-membrane-coating methods include (1) physical extrusion, where nanoagent cores and membrane vesicles are repeatedly passed through a porous membrane; (2) ultrasonic coating, which uses ultrasound to mix and co-incubate components with less material loss; (3) electrostatic interactions, where charge differences between the nanoagent core and membrane vesicles drive spontaneous coating; (4) electroporation, where macrophages engulf nanoagents, followed by an electric-field-induced release of cell contents; and (5) in situ packaging, where live cells secrete vesicles encapsulating NPs. These evolving strategies integrate macrophage membranes with NPs for enhanced therapeutic potential.