Nanoerythrocyte Membrane–Enveloped ROS-Responsive 5-Aminolevulinic Acid Prodrug Nanostructures with Robust Atheroprotection

The development of smart nanoagents that can respond to a specific stimulus has gained remarkable interest for treating various kinds of diseases, including atherosclerosis. On the other hand, a cell camouflaging strategy has been considered as a pivotal factor to improve the delivery stealthiness, biocompatibility, and biodegradability of nanocarriers, resolving the shortcomings of PEGylation. In this study, reactive oxygen species (ROS)-responsive 5-aminolevulinic acid (ALA) prodrug nanostructures (ROSELLA) encapsulating rapamycin (RAP) are blended with nanoerythrocyte membranes to construct red blood cell membrane (RBCM)/RAP@ROSELLA. These nanoagents are designed to be able to escape the biological barriers, accumulate in atherosclerosis lesions, and enhance the release of drugs in the intracellular milieu due to the magnification of hydrogen peroxide (H 2 O 2 ). In vitro study proves its superior ability to inhibit the proliferation of macrophages and vascular smooth muscle cells. In vivo developmental toxicity further confirms that no significant systematic toxicity is induced by RBCM/RAP@ROSELLA, implying its favorable biocompatibility, which has potential for precise nanomedicine to combat atherosclerosis.