Most chemotherapeutic drugs and their nanomedicine formulations exert anticancer activity by inducing cancer cell apoptosis. However, cancer cells inherently have and acquire many antiapoptosis mechanisms, causing cancer drug resistance and poor prognoses in patients. Herein, a potent paraptosis-inducing nanomedicine is reported that causes quick nonapoptotic death of cancer cells, overcoming apoptosis-based resistance and effectively inhibiting drug-resistant tumor growth. The nanomedicine is composed of micelles made from an amphiphilic 8-hydroxyquinoline (HQ)-conjugate block copolymer with polyethylene glycol. Cu2+ can catalyze the hydrolysis of the HQ conjugation linker and liberate HQ, and these molecules can form the complex Cu(HQ)2 , a strong proteasome inhibitor effective at inducing cell paraptosis. In vivo, the Cu2+ -responsive HQ-releasing micelles respond to elevated tumor Cu2+ levels or externally administered Cu2+ and effectively inhibit the growth of human breast adenocarcinoma doxorubicin-resistant (MCF-7/ADR) tumors. Compared with other nanomedicines that overcome drug resistance via delivering several agents or even siRNA, this paraptosis-inducing nanomedicine provides a simple but potent approach to overcoming cancer drug resistance.