Nanozyme-engineered stress-resistant microalgae S.t.@CuMgHCF for tumor microenvironment regulation

Excessive reactive oxygen species (ROS) and hypoxia in the tumor microenvironment (TME) severely limit the efficacy of cancer therapies. Photosynthetic microalgae can supply oxygen to relieve hypoxia, but their therapeutic utility is constrained by poor oxidative stress resistance. To overcome this limitation, we engineered the marine microalga Scrippsiella trochoidea (S.t.) with CuMg bimetallic hexacyanoferrate (CuMgHCF) nanozymes-which exhibit cascade superoxide dismutase (SOD)- and catalase (CAT)-like activities-via electrostatic anchoring, yielding S.t.@CuMgHCF. We also developed a ferrocene-labeled DNA sensor on a platinum nanoelectrode to monitor intracellular ROS dynamics in single cells using fast-scan voltammetry. Under simulated TME conditions, S.t.@CuMgHCF showed markedly lower intracellular ROS and malondialdehyde levels, along with higher chlorophyll a retention, than unmodified algae. In co-cultures with diverse cancer cell lines, S.t.@CuMgHCF sustained light-triggered oxygen production and outperformed native microalgae in both two- and three-dimensional models. By integrating nanozyme-enhanced stress resistance with single-cell electrochemical sensing, this work establishes a strategy to counteract tumor hypoxia and improve therapeutic outcomes.