This study addresses the issue of off-target distribution of chemotherapeutic drugs, which leads to severe side effects and poor patient compliance. To overcome this, a novel strategy is proposed that activates prodrugs in the tumor microenvironment without affecting normal tissues. The researchers developed an ultrasound (US)-activated prodrug-loaded liposome (CPBSN38L) containing chlorin e6 (Ce6)-modified lipids and the prodrug of pinacol boronic ester-conjugated SN38 (PBSN38). When CPBSN38L accumulates in the tumor and is internalized into cancer cells, US irradiation triggers Ce6 to produce reactive oxygen species (ROS), which activate PBSN38 to release active SN38, inducing cell apoptosis. This approach demonstrates 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 study establishes a side-effect-free, universal, and feasible strategy for cancer-targeting therapy.This study addresses the issue of off-target distribution of chemotherapeutic drugs, which leads to severe side effects and poor patient compliance. To overcome this, a novel strategy is proposed that activates prodrugs in the tumor microenvironment without affecting normal tissues. The researchers developed an ultrasound (US)-activated prodrug-loaded liposome (CPBSN38L) containing chlorin e6 (Ce6)-modified lipids and the prodrug of pinacol boronic ester-conjugated SN38 (PBSN38). When CPBSN38L accumulates in the tumor and is internalized into cancer cells, US irradiation triggers Ce6 to produce reactive oxygen species (ROS), which activate PBSN38 to release active SN38, inducing cell apoptosis. This approach demonstrates 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 study establishes a side-effect-free, universal, and feasible strategy for cancer-targeting therapy.