Dismountable Protein Corona‐Modified Virus‐Like Manganese‐Arsenic Nanomedicine Enables Safe and Targeted Delivery for Synergistic Arsenotherapy

Abstract Arsenic agents have shown great potential in fighting leukemia, but are poorly known in treating solid tumors, mainly ascribing to the rapid clearance and low targeting ability. It is reported that morphology modulation can enhance the interaction between nanoparticles and cell membrane. Herein, a dismountable protein corona‐modified virus‐like manganese‐arsenic nanomedicine (vMnAs@HR) is rationally proposed for realizing safe and targeted delivery and synergistic arsenotherapy. The virus‐like manganese‐arsenic nanoparticle (vMnAs) is constructed followed by modification of a temporary R848‐loaded HDL (HR) protein corona. Upon intravenous injection, the HR protein corona is stable and actively targeted to tumor tissue by taking advantage of the interaction between HDL and its receptor SR‐BI. Intriguingly, upon accumulated in the tumor, HR can be jettisoned and interacted with macrophages for proinflammatory phenotype modulation. The re‐exposed vMnAs can efficiently enhance endocytosis by taking advantage of the rationally designed spiky morphology. Moreover, the released double‐stranded DNA (dsDNA) and manganese ions during tumor cell apoptosis can cooperatively activate cyclic guanosine monophosphate adenosine monophosphate synthase (cGAS)‐stimulator of interferon genes (STING) signaling pathway of DCs for systematic immune activation. It is anticipated that this morphology‐transformable nanomedicine can realize safe and efficient arsenic delivery for synergistic arsenotherapy.