Synergistic Gas Therapy and Targeted Interventional Ablation With Size‐Controllable Arsenic Sulfide (As2S3) 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. HA‐As2S3 nanoparticles are synthesized using sodium hyaluronate as a supramolecular scaffold. In acidic conditions, they release hydrogen sulfide and arsenic ions. Arsenic damages mitochondria, while hydrogen sulfide inhibits catalase and complex IV, disrupting ROS breakdown and electron transport. This synergy enhances mitochondrial damage, leading to ROS production from mitochondria, triggering apoptosis, and eliminating cancer pain.