Polytonic Drug Release via Multi‐Hierarchical Microstructures Enabled by Nano‐Metamaterials

Abstract ″Nano‐metamaterials″, rationally designed novel class metamaterials with multilevel microarchitectures and both characteristic sizes and whole sizes at the nanoscale, are introduced into the area of drug delivery system (DDS), and the relationship between release profile and treatment efficacy at the single‐cell level is revealed for the first time. Fe 3+ ‐core‐shell‐corona nano‐metamaterials (Fe 3+ ‐CSCs) are synthesized 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. A novel polytonic drug release profile occurred, which consists of three sequential stages: burst release, metronomic release, and sustained release. The Fe 3+ ‐CSCs results in overwhelming accumulation of lipid reactive oxygen species (ROS), cytoplasm ROS, and mitochondrial ROS in tumor cells and induces unregulated cell death. This cell death modality causes cell membranes to form blebs, seriously corrupting cell membranes to significantly overcome the drug‐resistance issues. It is first demonstrated that nano‐metamaterials of well‐defined microstructures can modulate drug release profile at the single cell level, which in turn alters the downstream biochemical reactions and subsequent cell death modalities. This concept has significant implications in the drug delivery area and can serve to assist in designing potential intelligent nanostructures for novel molecular‐based diagnostics and therapeutics.