Simultaneously delivery of functional gallium ions and hydrogen sulfide to endow potentiated treatment efficacy in chemo- and PARPi-resistant ovarian cancer

Platinum-resistant ovarian cancer (OC) presents limited therapeutic options. In this study, we developed gallium sulfide-embedded bovine serum albumin nanoformulations (Ga2S3-BSA NMs) with a size of approximately 11 nm, created through a self-assembly approach. These nanoformulations degrade in the acidic microenvironment of cancer cells, releasing Ga3+ and H2S gas, which work together to exert anticancer effects. In platinum-resistant OC cell lines A2780-CIS and SKOV3-CIS, the release of Ga3+ and H2S from Ga2S3-BSA NMs synergistically induced DNA damage, arrested the cell cycle at the S and G2/M phases, and inhibited cell proliferation. Additionally, Ga2S3-BSA NMs significantly suppressed NF-κB signaling and Bcl2 protein expression, promoting apoptosis. The nanoformulations also increased lipid peroxidation and triggered ferroptosis. RNA sequencing analysis further elucidated the comprehensive antitumor mechanisms of Ga2S3-BSA NMs. Importantly, in a platinum-resistant OC animal model, Ga2S3-BSA NMs demonstrated significant therapeutic efficacy and enhanced sensitivity to carboplatin and fluzoparib, with minimal toxicity. Overall, our findings highlight Ga2S3-BSA NMs as a promising and practical strategy to overcome drug SHR-3162 resistance in platinum-resistant OC.