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

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-As₂S₃ 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 (As³⁺) via coordinate bonds, forming HA-As³⁺ scaffold intermediates. These intermediates, varying in size, then react with sulfur ions to produce size-controlled HA-As₂S₃ 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-As₂S₃ nanoparticles release hydrogen sulfide(H₂S) gas and As³⁺. The released As³⁺ directly damage tumor mitochondria, leading to substantial reactive oxygen species (ROS) production from mitochondria. Concurrently, the H₂S 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 H₂S gas significantly enhances the mitochondrial damage induced by arsenic nanodrugs, effectively killing local tumors and ultimately eliminating cancer pain in mice.