In-situ gas nanogenerator for pH-responsive controlled release and H2S-chemo combined therapy in vitro

Developing smart nanosystems that integrate controlled drug release with gas therapy represents a promising strategy to enhance chemotherapeutic efficacy while minimizing systemic toxicity. Herein, we report a biodegradable in-situ hydrogen sulfide (H2S) nanogenerator based on ZnS nanoparticles (NPs) for pH-responsive co-delivery of H2S and doxorubicin (DOX). ZnS NPs were synthesized via a rapid hydrothermal method and subsequently functionalized with hyaluronic acid (HA) to form ZnS@HA, which was then electrostatically loaded with DOX to yield ZnS@HA-DOX NPs. The nanosystem maintains structural integrity under physiological conditions (pH 7.4) but selectively releases both DOX and H2S under acidic tumor microenvironment (pH 5.0), as confirmed by fluorescence spectroscopy, lead acetate paper assays, and WSP-1 probe-based quantification. In vitro studies using 4T1 breast cancer cells revealed that ZnS@HA-DOX NPs exhibit significant cytotoxicity compared to ZnS@HA NPs alone, indicating a synergistic effect between H2S gas therapy and chemotherapy. This work demonstrates the potential of ZnS-based nanogenerators as a multifunctional platform for pH-triggered, site-specific, and synergistic cancer therapy.