Hijacking Self‐Assembly to Establish Intracellular Functional Nanoparticles

The targeted transport of nanomedicines is often impeded by various biological events in the body. Viruses can hijack host cells and utilize intracellular transcription and translation biological events to achieve their replication. Inspired by this, a strategy to hijack endogenous products of biological events to assemble into intracellular functional nanoparticles is established. It has been shown that, following tumor vessel destruction therapy, injected cell permeable small molecule drugs bisphosphonate can hijack the hemorrhagic product iron and self‐assemble into peroxidase‐like nanoparticles within tumor‐infiltrating macrophages. Unlike free drugs, the generated intercellular nanoparticles can specifically stress mitochondria, resulting in immune activation of macrophages in vitro and polarizing tumor‐associated macrophages (TAMs) from immunosuppressive to tumoricidal and increasing the recruitment of T cells deep within tumor. The hijacking self‐assembly strategy significantly inhibits tumor growth compared with the treatment of vascular‐disrupting agents alone. Using bisphosphonate to hijack the metabolite associated with hemorrhage, iron, to fabricate functional nanoparticles within specific cells, which may open up new nanotechnology for drug delivery and small molecular drug development. Systemically injected small molecule agents bisphosphonate react with endogenous ferrous iron, the product of erythrocyte degradation, and finally self‐assembly into functional nanoparticles to regulate the behavior of cells. This virus‐inspired hijacking self‐assembly strategy brings new clinically feasible nanotechnology for the cell targeting and action mode of small molecule agents.