Tumor Microenvironment Self-Propelled Nanoreactors for Synergistic Cancer Chemodynamic–Gene Therapy

In view of improved therapeutic efficacies compared to sole therapy, combination therapy strategies show great potential in cancer treatment, but their therapeutic efficacies are still severely limited by the inefficient targeted delivery of therapeutic agents. This study reports a tumor microenvironment (TME) self-propelled nanoreactor system for synergistic chemodynamic therapy (CDT) and gene therapy. This system (termed Lip-GOx-MnO2-siRNA) is constructed using a reactive oxygen species (ROS)-responsive nanoreactor with coencapsulations of glucose oxidase (GOx), bovine serum albumin–manganese dioxide (BSA-MnO2) complex, and polo-like kinase 1 (PLK-1) siRNA. In a subcutaneous A549 xenograft model, the loaded GOx consumes intratumoral glucose to produce hydrogen peroxide (H2O2). This in situ generated H2O2 then initiates a Fenton-like reaction with the BSA-MnO2 component, yielding hydroxyl radicals (•OH) that potentiate the CDT. Moreover, the generated •OH triggers the cleavage of a thioketal (TK) linker in ROS-responsive nanoreactors, leading to the specific release of PLK-1 siRNA. As a result, the released siRNA silences the PLK-1 expression to inhibit tumor cell proliferation. Thus, Lip-GOx-MnO2-siRNA synergistically induces tumor cell apoptosis through self-enhanced •OH generation and gene silencing, leading to significant tumor growth suppression. This work presents a nanodelivery strategy for combining catalytic therapy with gene regulation.