Mechanically Regulated Nanozymes for Remote Metabolic Reprogramming and Precise Cancer Therapy.

Mechanoenzymes, featuring catalytic activity controlled by mechanical stimuli, play key roles in maintaining metabolic order and cellular homeostasis. However, artificial nanozymes with strict spatiotemporal regulation are still rare, limiting their effectiveness in complex biological environments. Here, we introduce a mechanically regulated nanozyme (MRNZ) by integrating mechano-responsive ferrocene (Fc) units into a flexible framework. Similar to natural enzymatic activation, acoustic shear forces cause sub-nanostructural transformations of Fc units, leading to decreased electron density and reduced steric hindrance at Fe active sites, reinforcing metabolic peroxidase (POD)-like activity. This mechanical activation enables precise modulation of metabolic reprogramming by controlled generation of low-dose hydroxyl radicals (•OH) as second messengers, improving stem cells resilience to oxidative stress for safer and more effective therapeutic interventions. Using this mechanically regulated method, we encapsulated glucose oxidase (GOx) inside hollow MRNZ to create a multienzyme regulated nanoreactor (MRNZ@GOx) that orchestrates a cascade GOx-POD reaction under ultrasound stimulation. Such a cascade reactive oxygen species generation in tumor microenvironments potentiates chemodynamic therapy combined with immune activation. Our work introduces a mechanically responsive strategy for regulating nanozyme activity, expanding the horizons of next-generation remote and smart catalytic technologies for precise disease treatments.