Nanogels confined superactive LOx-CPO for TME-responsive enzyme-gene therapy

Tumor cells, due to their reliance on aerobic glycolysis, contribute to the tumor microenvironment (TME), which is characterized by lactate accumulation and redox imbalances. Targeting lactate, a key metabolic substrate in the TME, a novel strategy combining gene therapy with enzyme dynamic therapy (EDT) has been proposed. This strategy utilizes a cascade oxidase-peroxidase system, which induces tumor DNA damage while simultaneously inhibiting repair mechanisms. By mimicking the construction of multienzyme complexes, a highly active and well-ordered oxidase-peroxidase and gene platform (ASO-miR21/DLC-NGs) has been developed. The platform is based on dextran-confined lactate oxidase (LOx) and chloroperoxidase (CPO) pairs, followed by small molecule monomer-induced diffusion-controlled self-terminating polymerization for efficient loading of Antisense Oligonucleotide targeting microRNA-21 (ASO-miR21). By precisely regulating the dimensions (nanoscale to microscale) and crosslinking density, this approach overcomes the limitations of traditional multi-enzyme systems, such as poor stability and inefficient substrate diffusion. The synergistic effects of DNA damage and anti-repair are achieved by catalytically regulating reactive oxygen species (ROS), which reverses the redox balance and downregulates miR21 expression, inhibiting tumor cell proliferation. The catalytic transformation research of metabolic substrates of abnormal tumor microenvironment and the multi-pathway design with the metabolic regulation can provide important insights for specialized or interdisciplinary researchers on the multipathway cancer therapy.