In the work, yolk-shell structured mesoporous organosilica nanoparticles (YSMONs) are successfully prepared by a mild alkalescent etching approach. The method is very convenient, in which mesostructured organosilica nanospheres are directly transformed into yolk-shell structures after etching with mild alkalescent solution (e.g. sodium carbonate solution). The prepared YSMONs have ethane-bridged frameworks, a monodisperse diameter (320 nm), a large pore volume (1.0 cm(3) g(-1)), a uniform mesopore (2.4 nm) and a high surface area (1327 m(2) g(-1)). In vitro cytotoxicity and hemolysis assays demonstrate the ethane-bridged YSMONs possess excellent biocompatibility and low hemolysis activity. In addition, the YSMONs show a high loading capacity up to 181 mu g mg(-1) for anti-cancer drug doxorubicin (DOX). Confocal laser scanning microscopy and flow cytometry analyses show that the DOX loaded YSMONs (YSMONs-DOX) can be effiectively internalized by multidurg resistant MCF-7/MDR human breast cancer cells. The chemotherapy against MCF-7/MDR cells demonstrate that the YSMONs-DOX possess higher therapeutic efficacy compared to that of free DOX, suggesting that the YSMONs synthesized by the mild alkalescent etching method have great promise as advanced nanoplatforms for biological applications. (C) 2018 Elsevier Inc. All rights reserved.