Tumor-specific liquid metal nitric oxide nanogenerator for enhanced breast cancer therapy

Nitric oxide (NO) modulates several cancer-related physiological processes and has advanced the development of green methods for cancer treatment and integrated platforms for combination or synergistic therapies. Although a nanoengineering strategy has been proposed to overcome deficiencies of NO gas or small NO donor molecules, such as short half-life, lipophilicity, non-selectivity, and poor stability, it remains challenging to prepare NO nanomedicines with simple composition, multiple functions and enhanced therapeutic efficacy. Herein, we build a liquid metal nanodroplet (LMND)-based NO nanogenerator (LMND@HSG) that is stabilized by a bioreducible guanylated hyperbranched poly(amido amine) (HSG) ligand. Mechanically, the tumor microenvironment specifically triggers a cascade process of glutathione elimination, reactive oxygen species (ROS) generation, and NO release. According to actual demand, the ROS and NO concentrations could be readily controlled by tuning the LMND and HSG feed amounts. Along with the intrinsic anticancer property of LMND (ROS-mediated apoptosis and anti-angiogenesis), LMND@HSG administration could further enhance tumor growth suppression compared with LMND and HSG alone. From this study, leveraging LMND for NO gas therapy provides more possibilities for the prospect of LMND-based anticancer nanomedicines.