Construction of structural-varied macrophage hitchhiking delivery systems and targeting performance validation via a...

Macrophage-based drug delivery systems (MDDSs) have garnered significant interest due to their inherent chemotactic properties. However, systematic methodologies for evaluating their migration and the effects of different drug-loading strategies remain insufficient. In this study, two structurally distinct MDDSs were developed to address this gap. Curcumin-loaded hollow silica nanoparticles (Cur-SHS) were utilized for intracellular endocytosis (Mφ-Cur-SHS), while their lipid-coated counterparts (Cur-SHS@lip) were anchored to the macrophage surface (Mφ-Cur-SHS@lip). A microfluidic chip platform mimicking normal and tumor-associated inflammatory microenvironments was established to dynamically evaluate the chemotactic behavior of both MDDSs. Assays demonstrated that the surface-bound system (Mφ-Cur-SHS@lip) achieved significantly higher targeting efficiency than the endocytosed system. The surface-anchored configuration reduced cytotoxicity and better preserved the intrinsic motility of macrophages, whereas excessive nanodrug loading impaired migration, underscoring the necessity of optimizing drug loading in macrophages. Furthermore, biodistribution study in tumor-bearing mice confirmed that both MDDSs effectively targeted tumor tissues. These findings provide critical insights into how structural configuration and drug loading influence the performance of MDDSs, and establish a robust microfluidic platform for the systematic evaluation and optimization of macrophage-based biomimetic delivery systems.