Mechano‐Responsive Leapfrog Micelles Enable Interactive Apoptotic and Ferroptotic Cancer Therapy

Abstract The combination of apoptosis and ferroptosis is highly appealing in addressing the tumor heterogeneity‐induced therapy resistance. Reactive oxygen species (ROS)‐based cancer nanomedicine can assemble multiple cell death modalities in a single platform, but the potency of ferroptosis induction is limited. Here, a novel mechano‐responsive polymeric micellar system for selective ferroptosis boosting and ROS therapy sensitization is reported. The mechanophore, ferrocene (Fc) is the key to such design, and the ultrasound can speed up the dissociation of Fc and the release of Fe 2+ and hydroxyl radical in the presence of elevated H 2 O 2 in the tumor microenvironment. The Fc‐conjugated amphiphilic copolymers self‐assemble into nanoscale micelles wherein a model sonosensitizer, protoporphyrin IX is physically encapsulated. Upon triggering, the mechano‐responsive micelles produce both singlet oxygen and hydroxyl radical for apoptotic cell death in a model murine breast cancer cell line (4T1). The ROS also depletes intracellular glutathione and thioredoxin, which together with the heightened Fe 2+ level boosts lipid peroxidation and hence ferroptotic cell death. The interactive apoptosis and ferroptosis induction and sensitization is further demonstrated in a 4T1 tumor‐bearing mice model with negligible adverse effects. The current work provides a novel approach to simultaneously sensitize apoptosis and ferroptosis for efficient on‐demand cancer therapy.