Synergistic Gas Therapy and Targeted Interventional Ablation With Size‐Controllable Arsenic Sulfide (As ₂ S ₃ ) Nanoparticles for Effective Elimination of Localized Cancer Pain

Abstract The elimination of localized cancer pain remains a globally neglected challenge. A potential solution lies in combining gas therapy with targeted interventional ablation therapy. In this study, HA‐As ₂ S ₃ nanoparticles with controlled sizes are synthesized using different molecular weights of sodium hyaluronate (HA) as a supramolecular scaffold. Initially, HA co‐assembles with arsenic ions (As ³⁺ ) via coordinate bonds, forming HA‐As ³⁺ scaffold intermediates. These intermediates, varying in size, then react with sulfur ions to produce size‐controlled HA‐As ₂ S ₃ particles. This approach demonstrates that different molecular weights of HA enable precise control over the particle size of arsenic sulfide, offering a straightforward and environmentally friendly method for synthesizing metal sulfide particles. In an acidic environment, HA‐As ₂ S ₃ nanoparticles release hydrogen sulfide(H ₂ S) gas and As ³⁺ . The released As ³⁺ directly damage tumor mitochondria, leading to substantial reactive oxygen species (ROS) production from mitochondria. Concurrently, the H ₂ S gas inhibits the activity of catalase (CAT) and complex IV, preventing the beneficial decomposition of ROS and disrupting electron transfer in the mitochondrial respiratory chain. Consequently, it is found that H ₂ S gas significantly enhances the mitochondrial damage induced by arsenic nanodrugs, effectively killing local tumors and ultimately eliminating cancer pain in mice.