Redox‐Responsive Dual Drug Delivery Nanosystem Suppresses Cancer Repopulation by Abrogating Doxorubicin‐Promoted Cancer Stemness, Metastasis, and Drug Resistance

Chemotherapy is a major therapeutic option for cancer patients. However, its effectiveness is challenged by chemodrugs' intrinsic pathological interactions with residual cancer cells. While inducing cancer cell death, chemodrugs enhance cancer stemness, invasiveness, and drug resistance of remaining cancer cells through upregulating cyclooxygenase‐2/prostaglandin‐E2 (COX‐2/PGE(2)) signaling, therefore facilitating cancer repopulation and relapse. Toward tumor eradication, it is necessary to improve chemotherapy by abrogating these chemotherapy‐induced effects. Herein, redox‐responsive, celecoxib‐modified mesoporous silica nanoparticles with poly(β‐cyclodextrin) wrapping (MSCPs) for sealing doxorubicin (DOX) are synthesized. Celecoxib, an FDA‐approved COX‐2 inhibitor, is employed as a structural and functional element to confer MSCPs with redox‐responsiveness and COX‐2/PGE(2) inhibitory activity. MSCPs efficiently codeliver DOX and celecoxib into the tumor location, minimizing systemic toxicity. Importantly, through blocking chemotherapy‐activated COX‐2/PGE(2) signaling, MSCPs drastically enhance DOX's antitumor activity by suppressing enhancement of cancer stemness and invasiveness as well as drug resistance induced by DOX‐based chemotherapy in vitro. This is also remarkably achieved in three preclinical tumor models in vivo. DOX‐loaded MSCPs effectively inhibit tumor repopulation by blocking COX‐2/PGE(2) signaling, which eliminates DOX‐induced expansion of cancer stem‐like cells, distant metastasis, and acquired drug resistance. Thus, this drug delivery nanosystem is capable of effectively suppressing tumor repopulation and has potential clinical translational value.