Nanozymes for extracellular matrix and cell sheet engineering: biomedical potential and complementary enzymatic...

Cell sheet engineering has emerged as a scaffold-free biofabrication strategy that preserves intrinsic cell-cell and cell-extracellular matrix interactions, demonstrating significant translational potential in regenerative medicine, including cardiac patches, cartilage and skin reconstruction, and corneal transplantation. Despite these advances, thick or multilayered cell sheets remain constrained by diffusion related hypoxia, accumulation of reactive oxygen species, ECM destabilization, and insufficient mechanical reinforcement, all of which interact to compromise long term structural integrity. Rather than providing a conventional survey of recent developments, this conceptual integration review reframes these limitations as a coupled reaction-diffusion-mechanics problem. We examine how redox imbalance and structural insufficiency form a self-reinforcing failure network in thick scaffold-free constructs and propose a reciprocal dual-axis catalytic framework to address this instability. Nanozymes, through catalase-, peroxidase-, and superoxide dismutase-like catalytic activities, regulate oxidative stress, alleviate hypoxic amplification, and establish a permissive redox microenvironment that sustains cell viability and ECM synthesis. In parallel, immobilized enzyme systems facilitate collagen crosslinking and protease modulation, thereby reinforcing ECM architecture and enhancing tensile and shear resilience at the network level. Although nanozyme-based redox regulation and enzyme-mediated structural reinforcement have been extensively explored in oncology, antioxidant therapeutics, and industrial catalysis, their coordinated implications for scaffold-free cell sheet engineering have not been systematically integrated. By articulating a reciprocal dual-axis framework linking redox stabilization with biomechanical maturation, this review provides a systems-level design logic for improving thick cell sheet stability. Finally, we extend this catalytic paradigm beyond regenerative medicine to high-density sheet-like biofabrication systems, including cultured meat and cultured leather, positioning the framework as a transferable engineering principle across emerging biofabrication industries.