Genetically Engineered Protein Corona‐based Cascade Nanozymes for Enhanced Tumor Therapy

Abstract The emergence of nanomedicine has provided a promising strategy to greatly enhance the therapeutic efficacy of O₂‐dependent photodynamic therapy (PDT). However, plasma‐derived protein corona and/or discontinuous O₂ supply substantially limit their tumor delivery efficiency and therapeutic outcomes. Herein, protein corona cloaking‐based cascade nanozymes are developed using genetically engineered human ferritin heavy chain nanocages (FTn) as unique pre‐coated protein corona and cascade nanozymes as steady O₂ suppliers. Specifically, FTn is coated onto mesoporous silica nanoparticles (MSNs) to form FTn‐based protein corona, providing active targeting of tumor cells by binding with its receptor. In situ synthesis of ultra‐small Au nanoparticles in MSNs, and biomimetic incorporation of Ru nanoclusters into FTn inner cavity showed glucose oxidase‐like activity and catalase‐like activity, respectively. The two nanozymes are incorporated into MSNs nanoplatform to induce cascade and circular catalytic reactions by consuming glucose and H₂O₂ within the tumor microenvironment. Compared to MSNs alone, the FTn‐based protein corona is capable of efficiently diminishing plasma‐derived protein corona formation to prolong blood circulation time and improving in vitro tumor cell uptake and in vivo tumor accumulation, thereby providing significantly enhanced therapeutic benefits of PDT by combining with the continuously produced O₂ of cascade nanozymes.