Acid‐Unlocked Switch Controlled the Enzyme and CO In Situ Release to Induce Mitochondrial Damage via Synergy

Abstract CO gas therapy has attracted enormous attention in tumor therapy due to the abilities of mitochondrial damage and inhibition of cellular respiration. However, the inefficient and random release of CO greatly limit its application. Taking this into account, the study constructs an acid‐unlocked nanostructure based on MPDA‐MnCO‐GOx@DSNPs, designated as MMGD. The nanostructure enables tumor microenvironment (TME) specific enzyme and CO prodrug (manganese carbonyl, MnCO) cascade reaction, thus facilitating CO release in situ. Mesoporous polydopamine (MPDA) can provide the space for MnCO and glucose oxidase (GOx) loading. Especially, lanthanide (Ln 3+ )‐doped down‐shifting luminescent nanoparticles (DSNPs) can not only serve as the near‐infrared II (NIR‐II) fluorescence imaging probe, but also act as the acid‐unlocked gating switch. The slightly acidic TME can render the dissociation of DSNPs, thus exposing GOx and releasing MnCO. The catalytic reaction of GOx can produce H 2 O 2 and create a more acidic environment, which facilitates the CO generation in situ, leading to mitochondrial damage by reducing cytochrome c oxidase activity and adenosine triphosphate (ATP) levels. Meanwhile, MPDA has the NIR light absorption capability for photothermal therapy (PTT). This study provides an ingenious strategy for efficient and controllable CO gas, starvation, and PTT of tumor guided by NIR‐II fluorescence imaging.