Nanosized Glutathione- and Enzyme-Sensitive Carriers Based on Hyaluronic Acid for Hydrophilic Payload Delivery

Redox-responsive nanocarriers (NCs) for drug delivery have gained continuous interest in precision medicine. However, the complexity of the redox balance between different oxidative (e.g., reactive oxygen species) and antioxidative (e.g., glutathione, GSH) species in various pathological conditions (e.g., tumors, inflammation) makes site-specific payload release challenging. Moreover, hydrophilic bioactive substances undergo rapid clearance by the reticuloendothelial system. These obstacles underscore the necessity for novel strategies to enhance the precision and safety of redox-responsive NCs for hydrophilic payload delivery. Herein, we present a simple and efficient approach to fabricate hydrophilic cargo-loaded dual-responsive hyaluronic acid (HA)-based NCs using inverse miniemulsion interfacial cross-linking chemistry. By simply combining HA and bis(4-hydroxyphenyl) disulfide (HPD) as separate precursors in the formulation (i.e., without the need for prior chemical conjugation of HA and HPD), biopolymer-based NCs sensitive to hyaluronidase and GSH are achieved. A fluorescent dye, sulforhodamine B, and an anticancer drug, doxorubicin (DOX), were used as payloads. The characterization of NCs using dynamic light scattering and transmission electron microscopy exhibited <200 nm size with a narrow distribution and a core–shell nanocapsule morphology. We successfully obtained NCs with an encapsulation efficiency >90%, and the release studies showed that the encapsulated payloads were liberated in a sustained and controlled manner upon exposure to both GSH and enzymatic triggers at varying concentrations. In in vitro studies, no noticeable cytotoxicity was observed when human-derived dental pulp stem cells and lung cancer cells (A549) were exposed to NCs (up to 100 μg/mL), and a decrease in cell viability of A549 cells was observed with increasing concentrations of DOX-loaded NCs. Moreover, the NCs were internalized in the cells after 24 h of exposure. These dual-responsive, biocompatible, and biodegradable NCs have enormous scope in the delivery of hydrophilic therapeutics to treat various life-threatening ailments.