One‐Step Microfluidic Synthesis of Nanocomplex with Tunable Rigidity and Acid‐Switchable Surface Charge for Overcoming Drug Resistance

Multidrug resistance (MDR), is the key reason accounting for the failure of cancer chemotherapy, remains a dramatic challenge for cancer therapy. In this study, the one‐step microfluidic fabrication of a rigid pH‐sensitive micellar nanocomplex (RPN) with tunable rigidity and acid‐switchable surface charge for overcoming MDR by enhancing cellular uptake and lysosome escape is demonstrated. The RPN is composed of a poly(lactic‐co‐glycolic acid) (PLGA) core and a pH‐sensitive copolymer shell, which is of neutral surface charge during blood circulation. Upon internalization of RPN by cancer cells, the pH‐responsive shell dissociates inside the acidic lysosomes, while the rigid and positively charged PLGA core improves the lysosomal escape. The cellular uptake and nuclear uptake of doxorubicin (Dox) from Dox‐loaded RPN are 1.6 and 2.4 times higher than that from Dox‐loaded pH‐sensitive micelles (PM) using a Dox‐resistant cancer model (MCF‐7/ADR, re‐designated NCI/ADR‐RES) in vitro. Dox‐loaded RPN significantly enhances the therapeutic efficacy (92% inhibition of tumor growth) against MCF‐7/ADR xenograft tumor in mice, while Dox‐loaded PM only inhibits the tumor growth by 36%. RPN avoids the use of complicated synthesis procedure of nanoparticle and the necessary to integrate multiple components, which can facilitate the clinical translation of this novel nanostructure.