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A biocompatible and modifiable protein nanocarrier is a promising candidate for tumor targeted drug delivery. However, it is challenging to effectively load hydrophobic drugs, not to mention to upload both hydrophilic and hydrophobic drugs on one protein nanocarrier. Here, an amphiphilic multi‐drug loading protein nanocage (Am‐PNCage) is presented which is generated by replacing the fifth helix of human H‐ferritin (HFn) subunit with a functional motif composed of hydrophobic–hydrophilic‐RGD peptides. The Am‐PNCage possesses a dual targeting property resulting from the intrinsic CD71 targeting ability of HFn and the integrin α vβ3 targeting ability of displayed RGD peptides. Through the hydrophilic drug entry channel in the protein nanocage and hydrophobic peptides displayed on the outer surface, amphiphilic epirubicin (132)/camptothecin (50) are stereoscopically loaded into the inner cavity/outer protein shell, respectively, for one Am‐PNCage, exhibiting cascade drug release pattern. The dual‐targeted Am‐PNCage promotes the loaded drugs penetrating various 3D tumor models in vitro, as well as traversing the brain blood barrier and accumulating in brain tumors in vivo. Moreover, the drug loaded Am‐PNCage shows reduced side effects and significantly enhances synergistic efficacy against brain tumor, metastatic liver cancers, and drug resistant breast tumor. Thus, the Am‐PNCage represents a novel promising protein nanocarrier for targeted combination chemotherapy. [ABSTRACT FROM AUTHOR]

Keywords: cascade drug release; dual-tumor targeting; hydrophilic/hydrophobic drugs; protein cage nanocarrier; synergistic chemotherapy EN cascade drug release dual-tumor targeting hydrophilic/hydrophobic drugs protein cage nanocarrier synergistic chemotherapy 1 1 1 07/19/21 20210701 NES 210701 In article number 2102004, Xiyun Yan, Kelong Fan, and co-workers present an amphiphilic multi-drug loading protein nanocage (Am-PNCage) with a dual-tumor targeting (CD71 and Integrin) property, which exhibits a spatiotemporally programmed cascade drug release pattern and kills drug-resistant tumor cells synergistically. Synergistic Chemotherapy: Bioengineered Dual-Targeting Protein Nanocage for Stereoscopical Loading of Synergistic Hydrophilic/Hydrophobic Drugs to Enhance Anticancer Efficacy (Adv. Funct. Cascade drug release, dual-tumor targeting, hydrophilic/hydrophobic drugs, protein cage nanocarrier, synergistic chemotherapy. [Extracted from the article]