Atomic‐Level Strain‐Engineered Piezoelectric Nanosheets for cGAS‐STING Activation

ABSTRACT The cGAS‐STING pathway, a cornerstone of innate immunity and a crucial bridge to adaptive immune responses, represents a promising frontier in cancer immunotherapy. However, achieving tumor‐specific activation and precise modulation of this pathway remains a significant challenge. Herein, we adopt an atomic‐level strain engineering strategy to synthesize oxygen vacancy‐enriched Cu‐doped ZnAl‐LDH nanosheets as an ultrasound (US)‐driven piezoelectric‐STING agonist. Both the structural characterizations and theoretical calculations confirm that Cu ion doping triggers the local atomic strain, oxygen vacancy generation, and bond length adjustment to optimize the d ‐band center and enhance the built‐in electric field, significantly enhancing piezoelectric catalytic activity. Under US, this piezoelectric catalysis generates reactive oxygen species to disrupt mitochondrial integrity, trigger mtDNA release, and activate cGAS‐STING pathway. Concurrently, Zn 2+ ions liberated in the acidic tumor microenvironment amplify STING signaling. The piezoelectric activity also reduces tumor interstitial fluid pressure to improve agonist penetration and immunotherapeutic efficacy. Furthermore, cuproptosis‐released damage‐associated molecular patterns enhance antigen presentation and establish a synergistic “cuproptosis‐innate immunity” cascade. This integrated strategy not only unveils a novel “piezoelectric catalysis‐Zn 2+ release‐cuproptosis triple amplified STING” regulatory pathway, but also provides a biodegradable material platform and theoretical framework for developing tumor microenvironment‐responsive and externally controlled immunotherapies.