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Elevating intratumoral levels of highly toxic reactive oxygen species (ROS) by nanocatalytic medicine for tumor‐specific therapy without using conventional toxic chemodrugs is recently of considerable interest, which, however, still suffers from less satisfactory therapeutic efficacy due to the relatively poor accumulation at the tumor site and largely blocked intratumoral infiltration of nanomedicines. Herein, an ultrasound (US)‐triggered dual size/charge‐switchable nanocatalytic medicine, designated as Cu‐LDH/HMME@Lips, is constructed for deep solid tumor therapy via catalytic ROS generations. The negatively charged liposome outer‐layer of the nanomedicine enables much‐prolonged blood circulation for significantly enhanced tumoral accumulation, while the positively charged Fenton‐like catalyst Cu‐LDH released from the liposome under the US stimulation demonstrates much enhanced intratumoral penetration via transcytosis. In the meantime, the co‐released sonosensitizer hematoporphyrin monomethyl ether (HMME) catalyze the singlet oxygen (1O2) generation upon the US irradiation, and deep‐tumoral infiltrated Cu‐LDH catalyzes the H2O2 decomposition to produce highly toxic hydroxyl radical (·OH) specifically within the mildly acidic tumor microenvironment (TME). The efficient intratumoral accumulation and penetration via the dual size/charge switching mechanism, and the ROS generations by both sonosensitization and Fenton‐like reactions, ensures the high therapeutic efficacy for the deep tumor therapy by the nanocatalytic medicine., This work provides a novel ultrasound (US)‐triggered dual size/charge‐switchable nanocatalytic medicine for deep solid tumor therapy by reactive oxygen species generation in responses to both the US and tumor microenvironment (TME), which is believed to provide a feasible and promising strategy for catalytic tumor‐specific therapy.