Dynamic-Covalent Mesoporous Silica Nanohybrid with pH/ROS-Responsive Drug Release for Targeted Tumor Therapy

Nanomedicine provides promising new methodologies for the treatment of tumors but still faces several limitations, including poor colloidal stability, uncontrollable drug release, and insufficient drug targeting. Herein, hyaluronic acid (HA) was used to modify the surface of mesoporous silica nanoparticles (MSNs) via a dynamic-covalent linker, phenylborate ester (PBAE), termed MA. The HA modifier provided enhanced colloidal stability to the hybrid nanoparticles. As expected, MA exhibited an improved biocompatibility and high potential for biomedical applications. Moreover, MA with a negatively charged surface effectively adsorbed the drug Doxorubicin (DOX) inside the carriers, ensuring minimal drug leakage. In an acidic and reactive oxygen species (ROS)-containing condition mimicking the tumor microenvironment, MA@DOX (MAD) continuously released its payloads, likely due to the cleavage of the pH/ROS-sensitive PBAE. Compared with free DOX, MAD had 2.2 times higher accessibility to tumor cells than free DOX. The favorable stability and cancer-selective drug release make this nanoformulation a promising platform for potent cancer treatment.