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Small molecules that interfere with nucleic acid are widely used in chemotherapy, however, improved delivery approaches are required to improve anti-tumor outcomes. Here, we present the development of an ultrasound-activatable porphyrin-phospholipid-liposome (pp-lipo) that responds to low intensity focused ultrasound (LIFU) for sonodynamic therapy (SDT). The pp-lipo is constructed by incorporating a small proportion of porphyrin (pyropheophorbide) conjugated lipid into a liposome formulation. This enables sonosensitization-induced lipid oxidation and efficient disruption of liposomes to release loaded doxorubicin (Dox). This results in increased Dox nuclear subcellular location and cytotoxicity in cancer cells in vitro upon pp-lipo exposure to LIFU. Following intravenous administration, LIFU enhanced deposition of Dox within tumor tissue, suppressed tumor growth, and also increased porphyrin near infrared tumor fluorescence. Thus, pp-lipo is a versatile carrier that can be extended to many ultrasound-controllable drug delivery applications.Porphyrin-lipid conferred liposomes with ultrasound-responsive properties.Drug release from pp-lipo was spatiotemporally controlled by ultrasound exposure.Ultrasound facilitated pp-lipo imaging-guided deep penetration of cargos.Dox-pp-lipo benefited from the synergy of sonodynamic therapy and chemotherapy.Pp-lipo is versatile and can be extended to many ultrasound-controllable deliveries.