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

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 AuPt3Cu nanozyme asymmetrically coated with a disulfide-bridged mesoporous silica shell (2sMSN) loaded with L-arginine, allowing autonomous propulsion under O2, NO, and NIR irradiation to achieve deep tumor penetration. Upon cellular internalization, the asymmetric architecture enables concurrent AuPt3Cu-catalyzed oxidation of glucose to H2O2 and GSH-responsive degradation of 2sMSN to release L-arginine, thereby coupling nonenzymatic NO generation through H2O2-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.