Macrophage membrane-derived pH-responsive nanovesicles to target tumor cells with integrin α4β1 receptor

In this study, we developed macrophage-derived nanovesicles (MNVs) to specifically target tumor cells. Initially, we chemically coupled hyaluronic acid (HA) with 3-(diethylamino)propylamine (DEAP; with a pK(b) value of approximately 7.0) to confer pH-responsive properties. The resulting polymer (HDEA) and chlorin e6 (Ce6, serving as a photosensitizing model drug) were incorporated into MNVs using a sonication process, resulting in Ce6-loaded HDEA@MNVs. Our experiments demonstrated that the integrin alpha 4 beta 1 expressed in MNVs selectively interacted with vascular cell adhesion molecule-1 (VCAM-1) in SK-N-MC tumor cells, leading to enhanced accumulation of MNVs within the tumor cells. Consequently, HDEA@MNVs exhibited significant accumulation within tumor cells, underwent structural destabilization at endosomal pH due to the protonation of pH-responsive DEAP within the HDEA@MNVs, and facilitated the release of Ce6. The released free Ce6 from MNVs exhibited improved effectiveness in photodynamic tumor therapy when exposed to laser irradiation. In vitro cell experiments demonstrated efficient internalization of HDEA@MNVs into tumor cells and high efficacy in photodynamic therapy.