Metal–Phenolic‐Network‐Coated Dendrimer–Drug Conjugates for Tumor MR Imaging and Chemo/Chemodynamic Therapy via Amplification of Endoplasmic Reticulum Stress

Abstract Amplification of endoplasmic reticulum stress (ERS) to realize enhanced cancer therapy has been considered to be unique in current cancer nanomedicine design. Herein, the design of metal–phenolic‐network‐coated dendrimer–drug conjugates as a novel theranostic nanoplatform based on ERS amplification is reported. In the design, acetylated generation‐5 poly(amidoamine) dendrimers are conjugated with an ERS drug, toyocamycin (Toy), through the attached phenylboronic acid moiety, and coated with an iron (Fe)–tannic acid (TF) network. The generated nanocomplexes with a size of 50.2 nm are stable under the physiological environment, and can rapidly release Toy under the tumor microenvironment due to the pH‐ and reactive‐oxygen‐species‐responsive boronic ester bonds to effectively inhibit the ERS‐mediated cancer cell adaptation. Meanwhile, the coated TF network enables the nanocomplexes to generate cytotoxic hydroxyl radicals through a Fenton reaction, amplifying the ERS for improved chemo/chemodynamic therapy of cancer cells in vitro and a xenografted breast tumor model in vivo. Moreover, the coating of TF also renders the complexes with an eminent r₁ relaxivity for in vivo T₁‐weighted tumor magnetic resonance imaging. The created intelligent nanocomplexes may represent an advanced nanomedicine formulation uniquely integrated with a metal–phenolic network and dendrimer nanotechnology for imaging‐guided cancer therapy through ERS amplification.