A novel ultrasound-activated prodrug-loaded liposome (CPBSN38L) was developed for efficient cancer targeting therapy without chemotherapy-induced side effects. This strategy involves the use of a sonosensitizer, chlorin e6 (Ce6)-modified lipids, and a prodrug of pinacol boronic ester-conjugated SN38 (PBSN38). Once CPBSN38L accumulates in the tumor and is internalized by cancer cells, ultrasound irradiation triggers the production of reactive oxygen species (ROS), which activate PBSN38 to release active SN38, inducing cell apoptosis. In contrast, inactive PBSN38 in normal tissues does not exert pharmacological activity, minimizing side effects. CPBSN38L demonstrated strong anticancer activity in multiple murine tumor models of colon adenocarcinoma and hepatocellular carcinoma, with no chemotherapy-induced side effects compared to standard first-line drugs like irinotecan and topotecan. The strategy is independent of the tumor microenvironment and offers a side-effect-free, universal, and efficient approach for cancer targeting therapy. The liposome is stable, biocompatible, and capable of targeted drug delivery, making it a promising candidate for clinical applications.A novel ultrasound-activated prodrug-loaded liposome (CPBSN38L) was developed for efficient cancer targeting therapy without chemotherapy-induced side effects. This strategy involves the use of a sonosensitizer, chlorin e6 (Ce6)-modified lipids, and a prodrug of pinacol boronic ester-conjugated SN38 (PBSN38). Once CPBSN38L accumulates in the tumor and is internalized by cancer cells, ultrasound irradiation triggers the production of reactive oxygen species (ROS), which activate PBSN38 to release active SN38, inducing cell apoptosis. In contrast, inactive PBSN38 in normal tissues does not exert pharmacological activity, minimizing side effects. CPBSN38L demonstrated strong anticancer activity in multiple murine tumor models of colon adenocarcinoma and hepatocellular carcinoma, with no chemotherapy-induced side effects compared to standard first-line drugs like irinotecan and topotecan. The strategy is independent of the tumor microenvironment and offers a side-effect-free, universal, and efficient approach for cancer targeting therapy. The liposome is stable, biocompatible, and capable of targeted drug delivery, making it a promising candidate for clinical applications.