Polytonic drug release via multi- hierarchical microstructures enabled by nano-metamaterials.

We introduced "nano-metamaterials", rationally designed novel class metamaterials with multilevel microarchitectures and both characteristic sizes and whole sizes at nanoscale, into the area of drug delivery system, and the relationship between release profile and treatment efficacy at single-cell level is revealed for the first time. We synthesized Fe 3+ -core-shell-corona nano-metamaterials (Fe 3+ -CSCs) using a dual-kinetic control strategy. The hierarchical structure of Fe 3+ -CSCs, with a homogeneous interior core, an onion-like shell, and a hierarchically porous corona, was structurally similar to cells. Functionally inspired by the different transmission forms in living cells, a novel polytonic drug release profile occurred, which consists of three sequential stages: burst release, metronomic release, and sustained release. Compared with the monotonic continuous release of Fe 3+ from the homogeneous Fe 3+ -P2VP nanoparticles, which catalyzed Fenton-like reaction, produced lipid reactive oxygen species (ROS) and caused ferroptotic cell death; the polytonic Fe 3+ release of Fe 3+ -CSCs resulted in overwhelming accumulation of lipid ROS, cytoplasm ROS, and mitochondrial ROS in tumor cells and induced unregulated cell death. This cell death modality caused cell membranes to form blebs, seriously corrupting cell membranes to significantly overcome the drug-resistance issues. We first demonstrated that nano-metamaterials of well-defined microstructures can modulate drug release profile at single cell level, which in turn alters the downstream biochemical reactions and subsequent cell death modalities. This concept, therefore, has significant implications in drug delivery area and can serve to assist in designing potential intelligent nanostructures for novel molecular-based diagnostics and therapeutics. This article is protected by copyright. All rights reserved.