Double‐Layered Hollow Mesoporous Cuprous Oxide Nanoparticles for Double Drug Sequential Therapy of Tumors

Cancer stem cells (CSCs) are one of the determinants of tumor heterogeneity and are characterized by self-renewal, high tumorigenicity, invasiveness, and resistance to various therapies. To overcome the resistance of traditional tumor therapies resulting from CSCs, a strategy of double drug sequential therapy (DDST) for CSC-enriched tumors is proposed in this study and was realized utilizing our developed double layered hollow mesoporous cuprous oxide nanoparticles (DL-HMCONs). The high drug loading contents of camptothecin (CPT) and all-trans retinoic acid (ATRA) demonstrate that our DL-HMCON can be used as a generic drug delivery system (DDS). ATRA and CPT can be sequentially loaded in and released from CPT3@ATRA3@DL-HMCON@HA. The DDST mechanisms of CPT3@ATRA3@DL-HMCON@HA for CSC-containing tumors have been demonstrated as follows: 1) the first release of ATRA from the outer layer induces differentiation from CSCs with high drug resistance to non-CSCs with low drug resistance; 2) the second release of CPT from the inner layer causes apoptosis of non-CSCs; and 3) the third release of Cu+ from DL-HMCON itself triggers the Fenton-like reaction and GSH depletion, resulting in ferroptosis of non-CSCs. Our CPT3@ATRA3@DL-HMCON@HA has been verified to possess high DDST efficacy for CSC-enriched tumors with high biosafety. This article is protected by copyright. All rights reserved.