A shielded cascade of targeted nanocarriers spanning multiple microenvironmental barriers for inflammatory disease therapy.

Background: The multi-biological barriers present in the inflammatory microenvironment severely limit the targeted aggregation of anti-inflammatory drugs in the lesion area. However, conventional responsive drug carriers inevitably come into contact with several pro-responsive stimulatory mediators simultaneously, leading to premature drug release and loss of most therapeutic effects. Breaking through the multi-level barriers of the inflammatory microenvironment is essential to improve the enrichment and bioavailability of drugs.

Results: In this study, we propose a novel two-stage structural strategy to build shielded cascades of targeted nanocarriers (FA-PTP@Que) through inflammatory mediators, using cascade structures to cross multiple environmental barriers. The cascade structure of FA-PTP@Que is responsive to inflammatory mediators and exhibits ideal pathological microenvironmental response and drug release properties. FA-PTP@Que has shown good macrophage regulation and anti-inflammatory effects by efficiently targeting macrophages, scavenging intracellular reactive oxygen species (ROS), and down-regulating the secretion of pro-inflammatory factors. Significantly, in mice with arthritis and colitis, FA-PTP@Que enriches and targets macrophages at the sites of arthritis and colitis, showing significant anti-inflammatory effects.

Conclusion: FA-PTP@Que combines active chemotaxis of nanocarriers to inflammatory tissues and active targeting of effector cells, acting precisely at each barrier level in different microenvironments by responding to inflammatory mediators and overcoming the multiple barriers in the inflammatory microenvironment. This innovative strategy can effectively break through various inflammatory microenvironments and has the potential application to other inflammatory diseases.