Intracellular Co-delivery of proteins and chemotherapeutics using calcium carbonate mineralized nanoparticles for osteosarcoma therapy

Abstract

Intracellular co-delivery of proteins and chemotherapeutics provides a promising strategy for synergistic cancer therapy. However, the lack of delivery systems for controlled intracellular release of both payloads and effective endosomal escape of proteins significantly hinders the anticancer applications of this strategy. Herein, we designed a pH-responsive calcium carbonate mineralization nanoparticle system for concurrent delivery of cytochrome c (Cyt c) and doxorubicin (DOX) into the cytosol. The dual-drug loaded nanoparticles (CaNP/DOX/Cyt c) exhibited high stability under physiological conditions but acid-sensitive intracellular release of DOX and Cyt c, and also mediated efficient endosomal escape of Cyt c. As a result, the DOX underwent efficient delivery into the nuclei, and Cyt c successfully got into the cytosol as demonstrated by the confocal laser scanning microscopy. Furthermore, CaNP/DOX/Cyt c mediated enhanced synergistic anti-osteosarcoma effects with significantly improved biocompatibility as demonstrated both in vitro and in vivo. In summary, this work highlights the potential of calcium carbonate mineralized nanoparticle system as a universal and potent platform for efficient intracellular co-delivery of proteins and chemotherapeutics.