Asymmetric Structure‐Driven Functional Synergy: A Multistimuli‐Activated Janus Nanomotor for Self‐Amplifying NO Cascade Therapy

ABSTRACT Nitric oxide (NO)‐based cancer therapy is fundamentally limited by poor intratumoral penetration of exogenous donors and their inability to sustain localized relevant flux. Here, a multistimuli‐activated Janus nanomotor was developed to interconnect nonenzymatic and enzymatic NO‐generation pathways, enabling in situ self‐cascading NO production. The nanomotor comprises an AuPt 3 Cu nanozyme asymmetrically coated with a disulfide‐bridged mesoporous silica shell (2sMSN) loaded with L‐arginine, allowing autonomous propulsion under O 2, NO, and NIR irradiation to achieve deep tumor penetration. Upon cellular internalization, the asymmetric architecture enables concurrent AuPt 3 Cu‐catalyzed oxidation of glucose to H 2 O 2 and GSH‐responsive degradation of 2sMSN to release L‐arginine, thereby coupling nonenzymatic NO generation through H 2 O 2 ‐mediated L‐arginine oxidation. Subsequently, the resulting nitrosative stress suppresses glycolysis and drives compensatory pentose phosphate pathway activation, thereby increasing cofactor availability and enhancing nitric oxide synthase–dependent NO production. This self‐amplifying NO loop further amplifies mild photothermal therapy by inducing HSP90 downregulation, thereby triggering immunogenic cell death and achieving effective melanoma clearance. Overall, this Janus nanomotor presents an “asymmetric structure‐driven functional synergy” strategy for controllable, sustained, and uniform NO generation, offering a distinctive paradigm to overcome the intrinsic penetration and sustainability limitations of gas‐based therapeutic modalities.