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

Abstract 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 is realized utilizing the 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 the DL‐HMCON can be used as a generic drug delivery system. 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 are 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 glutathione depletion, resulting in ferroptosis of non‐CSCs. This CPT3@ATRA3@DL‐HMCON@HA is verified to possess high DDST efficacy for CSC‐enriched tumors with high biosafety.