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Nitric oxide (NO) plays a critical role as an important signaling molecule for a variety of biological functions, particularly inhibiting cell proliferation or killing target pathogens. To deliver active radical NO gaseous molecule whose half-life is a few seconds in a stable state, the design and development of effective exogenous NO supply nanocarriers are essential. Additionally, the delivery of desired drugs with NO can produce synergistic effects. Herein, we report a new approach that allows for the fabrication of dual ultrasound (US)/glutathione (GSH)-responsive perfluorocarbon (PFC) nanodroplets for the controlled release of model drug and passive release of safely incorporated NO. The approach centers on the synthesis of a disulfide-labeled amphiphilic block copolymer and its use as a GSH-degradable macromolecular emulsifier for oil-in-water emulsification process of PFC. The fabricated PFC nanodroplets are colloidally stable and enable the encapsulation of both NO and model drugs. Encapsulated drug molecules are synergistically released when ultrasound and GSH are presented, while NO molecules are passively but rapidly released. Our preliminary results demonstrate that the approach is versatile and can be extended to not only GSH-responsive but also other stimuli-responsive block copolymers, thereby allowing for the fabrication of broad choices of stimuli-responsive (smart) PFC-nanodroplets in aqueous solution for dual delivery of drug and NO therapeutics.